PNPLA6

Summary

PNPLA6 (patatin like domain 6, lysophospholipase , HGNC:16268) is a protein-coding gene on chromosome 19p13.2, encoding Patatin-like phospholipase domain-containing protein 6 (Q8IY17). Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).

This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome (Definitive, ClinGen) — +6 more curated relationships
• Clinical variants (ClinVar): 1,506 total — 72 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 116
• Druggable target: yes
• MANE Select transcript: NM_001166114

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16268
Approved symbol	PNPLA6
Name	patatin like domain 6, lysophospholipase
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	NTE, sws, iPLA2delta, SPG39
Ensembl gene	ENSG00000032444
Ensembl biotype	protein_coding
OMIM	603197
Entrez	10908

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 14 protein_coding, 10 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000221249, ENST00000414982, ENST00000450331, ENST00000545201, ENST00000593924, ENST00000594098, ENST00000594551, ENST00000594754, ENST00000594864, ENST00000595176, ENST00000595264, ENST00000595352, ENST00000595889, ENST00000596515, ENST00000597202, ENST00000598462, ENST00000599311, ENST00000599947, ENST00000599951, ENST00000600737, ENST00000600942, ENST00000601001, ENST00000601668, ENST00000602191, ENST00000646984

RefSeq mRNA: 5 — MANE Select: NM_001166114 NM_001166111, NM_001166112, NM_001166113, NM_001166114, NM_006702

CCDS: CCDS32891, CCDS54206, CCDS54207, CCDS59343

Canonical transcript exons

ENST00000600737 — 32 exons

Exon	Start	End
ENSE00000671211	7560648	7560764
ENSE00001053254	7550994	7551107
ENSE00001053260	7555607	7555763
ENSE00001053262	7554555	7554723
ENSE00001053276	7554209	7554272
ENSE00001053278	7540923	7541051
ENSE00001053282	7556453	7556569
ENSE00001053288	7558850	7559151
ENSE00001053293	7541354	7541434
ENSE00001053317	7556655	7556724
ENSE00001053321	7554893	7555075
ENSE00001116217	7555249	7555367
ENSE00001202485	7540630	7540710
ENSE00001720511	7557168	7557284
ENSE00003042815	7535717	7536020
ENSE00003498704	7561014	7561110
ENSE00003499616	7550298	7550429
ENSE00003504079	7543007	7543084
ENSE00003511730	7536191	7536273
ENSE00003512478	7561208	7561317
ENSE00003538724	7539918	7540058
ENSE00003541241	7561488	7561764
ENSE00003575145	7542761	7542928
ENSE00003579630	7551362	7551437
ENSE00003580235	7541522	7541684
ENSE00003580464	7550517	7550640
ENSE00003623568	7553875	7554015
ENSE00003632017	7540149	7540308
ENSE00003648465	7549907	7550112
ENSE00003649397	7541984	7542067
ENSE00003649724	7536449	7536546
ENSE00003786849	7542561	7542670

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 96.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4240 / max 128.5592, expressed in 1801 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173564	7.8732	1473
173562	6.1288	1593
173569	5.7858	1658
173568	0.1829	69
173571	0.1139	51
173565	0.1118	42
173566	0.0757	31
173573	0.0728	26
173574	0.0419	11
173575	0.0197	9

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.91	gold quality
metanephros cortex	UBERON:0010533	95.86	gold quality
upper lobe of left lung	UBERON:0008952	95.84	gold quality
right frontal lobe	UBERON:0002810	95.73	gold quality
adenohypophysis	UBERON:0002196	95.63	gold quality
mucosa of transverse colon	UBERON:0004991	95.60	gold quality
upper lobe of lung	UBERON:0008948	95.44	gold quality
right lung	UBERON:0002167	95.42	gold quality
right testis	UBERON:0004534	95.38	gold quality
spleen	UBERON:0002106	95.27	gold quality
left testis	UBERON:0004533	95.27	gold quality
apex of heart	UBERON:0002098	95.20	gold quality
lower esophagus mucosa	UBERON:0035834	94.92	gold quality
pituitary gland	UBERON:0000007	94.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.83	gold quality
cingulate cortex	UBERON:0003027	94.66	gold quality
anterior cingulate cortex	UBERON:0009835	94.57	gold quality
amygdala	UBERON:0001876	94.43	gold quality
prefrontal cortex	UBERON:0000451	94.37	gold quality
sural nerve	UBERON:0015488	94.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.21	gold quality
right adrenal gland cortex	UBERON:0035827	94.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.20	gold quality
right lobe of thyroid gland	UBERON:0001119	94.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.13	gold quality
monocyte	CL:0000576	94.09	gold quality
hypothalamus	UBERON:0001898	94.02	gold quality
right adrenal gland	UBERON:0001233	94.00	gold quality
mononuclear cell	CL:0000842	93.84	gold quality
caudate nucleus	UBERON:0001873	93.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, NFAT5

miRNA regulators (miRDB)

29 targeting PNPLA6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-503-5P	97.87	66.83	575

Literature-anchored findings (GeneRIF, showing 38)

• catalyzes hydrolysis of membrane lipids (PMID:11927584)
• Neuropathy target esterase and its homologues play a central role in membrane lipid homeostasis (PMID:15044461)
• All-trans retinoic acid -induced differentiation of the neuroblastoma cells with lowered NTE activity revealed that inhibition of NTE expression does not affect neural differentiation. (PMID:16010971)
• Results suggest that reduction of neuropathy target esterase does not affect process outgrowth or differentiation of neuroblastoma cells. (PMID:16122834)
• results suggest that the role of NTE over-expression in cell proliferation is associated with different mechanisms in different cells (PMID:16987144)
• These findings suggest that stimulation with phorbol 12-myristate 13-acetate reduces the expression of NTE mRNA levels but does not affect the exogenous promoter-driven NTE expression in mammalian cells. (PMID:17385009)
• NTE mutations in unrelated motor neuron disease patients indicate NTE’s importance in maintaining axonal integrity. (PMID:18313024)
• the macroautophagy/lysosome pathway plays a role in controlling NTE quantity, providing a further understanding of the function of NTE. (PMID:19059269)
• These results suggested for the first time that NTE is a cell cycle-dependent protein. (PMID:20306302)
• used the NTE catalytic domain (NEST) to hydrolyze palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (p-lysoPC) to palmitic acid in bilayer membranes comprising DOPC and NBD-PC (PMID:20346913)
• Endogenous NTE activity was increased by cAMP-elevating chemicals, but decreased by the adenyl cyclase inhibitor SQ22536 which can reduce intracellular cAMP levels. (PMID:20380879)
• The mutations found in association with NTE-related motor neuron disease have functional correlates in altered enzymological properties of NTE. (PMID:20382209)
• Lack of correlation between reduced fibroblast NTE SA and the occurrence of NTE-MND in NTE insertion mutation heterozygotes indicates that reduction of NTE SA alone is insufficient to cause notor neuron disease. (PMID:20603202)
• Mutations in the neuropathy target esterase (NTE) gene cause autosomal recessive motor neuron disease. The features of affected subjects in the index families are described. (PMID:21171093)
• Neuronal phospholipid deacylation is essential for axonal and synaptic integrity through the action of iPLA2 and NTE. (PMID:22903185)
• The activity of NTE was higher in Sick building syndrome patients compared with controls. Population with an AA genotype of a single nucleotide polymorphism, rs480208, in intron 21 of the PNPLA6 gene strongly reduced the activity of NTE. (PMID:23418070)
• PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system (PMID:24355708)
• These results suggest that hypogonadism-dependent alteration of phospholipid homeostasis in Gordon Holmes syndrome causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to the disease. (PMID:25033069)
• Silencing of PNPLA6, the neuropathy target esterase (NTE) codifying gene, alters early neurodevelopment. (PMID:25255935)
• Data confirm PNPLA6 mutations as the leading cause of Boucher-Neuhauser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. (PMID:25267340)
• Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase. (PMID:25480986)
• PNPLA6 has a role in photoreceptor survival; its mutations are linked to photoreceptor degeneration and various forms of childhood blindness (PMID:25574898)
• we found a novel compound heterozygous mutation and a novel homozygous one in the PNPLA6 gene in two Japanese patients with BNS. (PMID:25631098)
• inducible, neuron-specific expression of full-length human wildtype NTE reduces vacuole formation and substantially rescues mobility. (PMID:26671664)
• Data indicate two novel homozygous mutations (one frameshift and one missense mutation) detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for PNPLA6 (SPG39) and C19orf12 (SPG43). (PMID:26714052)
• These results strongly suggest that PNPLA9, -6 and -4 play a key role in GPL turnover and homeostasis in human cells. A hypothetical model suggesting how these enzymes could recognize the relative concentration of the different GPLs is proposed (PMID:27317427)
• The unusual medical history with childhood ataxia and hypogonadotropic hypogonadism lead to further examinations and eventually the diagnosis of BNS. The older sister of the proband also displayed the triad of ataxia, HH and chorioretinal dystrophy accompanied by cerebellar atrophy and in 2014, we found the mutations in PNPLA6. (PMID:27866050)
• This result further confirmed the role of PNPLA6 in BoucherNeuhauser syndrome (BNS) and suggested that whole exome sequencing may be applied for the diagnosis of complex syndromes, including BNS, prior to the observation of obvious symptoms. (PMID:29749493)
• CHORIORETINAL CHANGES IN A GENETICALLY CONFIRMED CASE OF BOUCHER-NEUHAUSER SYNDROME. (PMID:30015775)
• Bi-allelic variants in PNPLA6 possibly associated with Parkinsonian features in addition to spastic paraplegia phenotype. (PMID:32623594)
• Novel variants in PNPLA6 causing syndromic retinal dystrophy. (PMID:33141049)
• Reduced neuropathy target esterase in pre-eclampsia suppresses tube formation of HUVECs via dysregulation of phospholipid metabolism. (PMID:33184906)
• A novel PNPLA6 mutation in a Turkish family with intractable Holmes tremor and spastic ataxia. (PMID:33210227)
• Chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia: Boucher-Neuhauser syndrome due to a homozygous (c.3524C>G (p.Ser1175Cys)) variant in PNPLA6 gene. (PMID:33650466)
• Oliver McFarlane syndrome: two new cases and a review of the literature. (PMID:33818269)
• The alteration of the expression level of neuropathy target esterase in human neuroblastoma SK-N-SH cells disrupts cellular phospholipids homeostasis. (PMID:36336212)
• Two case reports of a novel missense mutation in the PNPLA6 gene in two siblings with chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar ataxia. (PMID:38683245)
• Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders. (PMID:38735647)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnpla6	ENSDARG00000010773
mus_musculus	Pnpla6	ENSMUSG00000004565
rattus_norvegicus	Pnpla6	ENSRNOG00000000977
drosophila_melanogaster	sws	FBGN0003656
caenorhabditis_elegans		WBGENE00022718

Paralogs (1): PNPLA7 (ENSG00000130653)

Protein

Protein identifiers

Patatin-like phospholipase domain-containing protein 6 — Q8IY17 (reviewed: Q8IY17)

Alternative names: Neuropathy target esterase

All UniProt accessions (11): A0A2R8Y7E1, A0A384DVU0, Q8IY17, M0QXH7, M0QYF5, M0QYT1, M0QZD1, M0QZK5, M0R2C2, M0R2H4, M0R2K2

UniProt curated annotations — full annotation on UniProt →

Function. Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Catalyzes the hydrolysis of several naturally occurring membrane-associated lipids. Hydrolyzes lysophospholipids and monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer. Does not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in brain, placenta, kidney, neuron and skeletal muscle. Expressed in the developing eye, pituitary and brain.

Post-translational modifications. Glycosylated.

Disease relevance. Spastic paraplegia 39, autosomal recessive (SPG39) [MIM:612020] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG39 is associated with a motor axonopathy affecting upper and lower limbs and resulting in progressive wasting of distal upper and lower extremity muscles. The disease is caused by variants affecting the gene represented in this entry. Boucher-Neuhauser syndrome (BNHS) [MIM:215470] An autosomal recessive disorder characterized by spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset is variable, but most patients develop 1 or more symptoms in the first decade of life. Chorioretinal dystrophy may not always be present. The disease is caused by variants affecting the gene represented in this entry. Laurence-Moon syndrome (LNMS) [MIM:245800] An autosomal recessive syndrome characterized by progressive spinocerebellar degeneration, spastic paraplegia, intellectual disability, hypogonadism, dwarfism, and chorioretinopathy. Trichomegaly is absent. The disease is caused by variants affecting the gene represented in this entry. Oliver-McFarlane syndrome (OMCS) [MIM:275400] A rare autosomal recessive, congenital syndrome characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies. It results in intellectual impairment and dwarfism, if untreated. Clinical features include hypogonadotropic hypogonadism during puberty, pigmentary retinal degeneration, ataxia, spastic paraplegia, and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by a series a OPs such as mipafox (MPX), phenyl saligenin phosphate (PSP), phenyl dipentyl phosphinate (PDPP), diisopropyl fluorophosphate and paraoxon.

Miscellaneous. Its specific chemical modification by certain organophosphorus (OP) compounds leads to distal axonopathy.

Similarity. Belongs to the NTE family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IY17-4	4	yes
Q8IY17-2	2
Q8IY17-3	3
Q8IY17-5	5

RefSeq proteins (5): NP_001159583, NP_001159584, NP_001159585, NP_001159586, NP_006693 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR001423	LysoPLipase_patatin_CS	Conserved_site
IPR002641	PNPLA_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR050301	NTE	Family
IPR056556	NTE1_P-loop_dom	Domain

Pfam: PF00027, PF01734, PF24179

Catalyzed reactions (Rhea), 9 shown:

• a 1-acyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + a fatty acid + H(+) (RHEA:15177)
• 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H2O = glycerol + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:26132)
• 1-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38487)
• 2-(9Z-octadecenoyl)-glycerol + H2O = glycerol + (9Z)-octadecenoate + H(+) (RHEA:38491)
• 1-hexadecanoylglycerol + H2O = glycerol + hexadecanoate + H(+) (RHEA:39959)
• 2-hexadecanoylglycerol + H2O = glycerol + hexadecanoate + H(+) (RHEA:39963)
• 1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + hexadecanoate + H(+) (RHEA:40435)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + (9Z)-octadecenoate + H(+) (RHEA:40807)
• 1-hexadecanoyl-sn-glycero-3-phosphate + H2O = sn-glycerol 3-phosphate + hexadecanoate + H(+) (RHEA:49092)

UniProt features (60 total): sequence variant 22, sequence conflict 7, modified residue 6, compositionally biased region 4, region of interest 4, short sequence motif 3, binding site 3, splice variant 3, topological domain 2, active site 2, chain 1, transmembrane region 1, glycosylation site 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IY17-F1	69.75	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 1014 (nucleophile); 1134 (proton acceptor)

Ligand- & substrate-binding residues (3): 195–322; 511–633; 629–749

Post-translational modifications (6): 354, 361, 362, 372, 420, 464

Glycosylation sites (1): 20

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6814848	Glycerophospholipid catabolism

MSigDB gene sets: 391 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, AACYNNNNTTCCS_UNKNOWN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GGAMTNNNNNTCCY_UNKNOWN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, HP1SITEFACTOR_Q6, HFH3_01, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS

GO Biological Process (6): phosphatidylcholine metabolic process (GO:0046470), glycerophospholipid catabolic process (GO:0046475), angiogenesis (GO:0001525), lipid metabolic process (GO:0006629), animal organ morphogenesis (GO:0009887), lipid catabolic process (GO:0016042)

GO Molecular Function (5): phosphatidylcholine lysophospholipase A1 activity (GO:0004622), B-type glycerophospholipase activity (GO:0102545), lipase activity (GO:0016298), hydrolase activity (GO:0016787), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycerophospholipid metabolic process	2
hydrolase activity, acting on ester bonds	2
cytoplasm	2
cellular anatomical structure	2
phospholipid catabolic process	1
glycerolipid catabolic process	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
primary metabolic process	1
anatomical structure morphogenesis	1
animal organ development	1
lipid metabolic process	1
catabolic process	1
lysophospholipase A1 activity	1
glycerophospholipase activity	1
carboxylic ester hydrolase activity	1
catalytic activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

2406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPLA6	SPART	Q8N0X7	882
PNPLA6	AP5Z1	O43299	866
PNPLA6	SPG7	Q9UQ90	866
PNPLA6	SPG21	Q9NZD8	860
PNPLA6	GJC2	Q5T442	859
PNPLA6	SPG11	Q96JI7	856
PNPLA6	ACHE	P22303	848
PNPLA6	MCOLN1	Q9GZU1	752
PNPLA6	PNPLA8	Q9NP80	734
PNPLA6	PNPLA4	P41247	681
PNPLA6	DDHD2	O94830	681
PNPLA6	CYP7B1	O75881	676
PNPLA6	DDHD1	Q8NEL9	646
PNPLA6	FA2H	Q7L5A8	611
PNPLA6	ZFYVE26	Q68DK2	610

IntAct

110 interactions, top by confidence:

A	B	Type	Score
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
EVA1C	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PLXDC2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PCDHB16	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
SLC30A4	OPA1	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
PNPLA6	PPIB	psi-mi:“MI:0915”(physical association)	0.400
TK	AP3B1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
BVLF1	VWA8	psi-mi:“MI:0914”(association)	0.350
PB2	HAX1	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB2	IPO5	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (160): PNPLA6 (Affinity Capture-RNA), PNPLA6 (Affinity Capture-RNA), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS), PNPLA6 (Affinity Capture-MS)

ESM2 similar proteins: A2AJ88, B3MRI9, B3NY03, B4H3U8, B4IL64, B4JLX2, B4L535, B4M709, B4N1W9, B4Q0P3, B5DKS8, D3ZEF4, O08703, O08962, O35219, O54853, P25848, P59111, P97414, Q02331, Q12809, Q14999, Q17QV9, Q21534, Q3TRM4, Q5BK26, Q5R667, Q5RCJ3, Q5RDS0, Q5TEA3, Q67E00, Q67E01, Q6CF18, Q6ZV29, Q7TNL3, Q7TT23, Q8IY17, Q8N2I9, Q8RY24, Q8VE73

Diamond homologs: A1C9L6, A1D9Y2, A2AJ88, A2R350, A3LYZ4, A4QVZ8, A5DHA3, A5E708, B3MRI9, B3NY03, B4H3U8, B4IL64, B4JLX2, B4L535, B4M709, B4N1W9, B4Q0P3, B5DKS8, P0AFR0, P0AFR1, P0CP36, P0CP37, Q02331, Q04958, Q0CNC7, Q0UJ42, Q1DLC7, Q21534, Q2H0D3, Q2UDH2, Q3TRM4, Q4PF83, Q4WA15, Q5A368, Q5BAE9, Q5BK26, Q5RDS0, Q6BQK9, Q6CF18, Q6CWC2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PNPLA6	“down-regulates quantity”	Lysophosphatidylcholine	“chemical modification”
PNPLA6	“up-regulates quantity”	2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425393	7	10.6×	8e-04
SLC-mediated transmembrane transport	11	7.6×	1e-04
Transport of small molecules	13	3.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of intracellular pH	6	33.4×	2e-05
sodium ion import across plasma membrane	5	28.9×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1506 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	72
Likely pathogenic	45
Uncertain significance	548
Likely benign	613
Benign	87

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101039	NM_001166114.2(PNPLA6):c.3143C>T (p.Thr1048Ile)	Pathogenic
101040	NM_001166114.2(PNPLA6):c.2185-1G>C	Pathogenic
101042	NM_001166114.2(PNPLA6):c.3167T>C (p.Phe1056Ser)	Pathogenic
1027427	NM_001166114.2(PNPLA6):c.43dup (p.Ala15fs)	Pathogenic
1065657	NM_001166114.2(PNPLA6):c.3202_3205dup (p.Ile1069fs)	Pathogenic
1071668	NM_001166114.2(PNPLA6):c.2285_2286dup (p.Ser763fs)	Pathogenic
1074568	NC_000019.9:g.(?7604804)(7607970_?)del	Pathogenic
1075623	NM_001166114.2(PNPLA6):c.2185-1G>T	Pathogenic
1172662	NM_001166114.2(PNPLA6):c.3885dup (p.Ser1296fs)	Pathogenic
1184929	NM_001166114.2(PNPLA6):c.459del (p.Glu153fs)	Pathogenic
1353395	NM_001166114.2(PNPLA6):c.1229dup (p.Ser411fs)	Pathogenic
1375988	NM_001166114.2(PNPLA6):c.2839_2840dup (p.Arg949fs)	Pathogenic
1377033	NM_001166114.2(PNPLA6):c.3296A>G (p.Tyr1099Cys)	Pathogenic
1381532	NM_001166114.2(PNPLA6):c.1692dup (p.Val565fs)	Pathogenic
1383806	NM_001166114.2(PNPLA6):c.1684_1685del (p.Cys562fs)	Pathogenic
1390532	NM_001166114.2(PNPLA6):c.897C>A (p.Tyr299Ter)	Pathogenic
1402204	NM_001166114.2(PNPLA6):c.2046C>A (p.Tyr682Ter)	Pathogenic
1421744	NM_001166114.2(PNPLA6):c.699_700del (p.Cys234fs)	Pathogenic
143933	NM_001166114.2(PNPLA6):c.1705G>T (p.Gly569Trp)	Pathogenic
1440677	NC_000019.10:g.7555609dup	Pathogenic
1452950	NM_001166114.2(PNPLA6):c.1606C>T (p.Gln536Ter)	Pathogenic
1455277	NM_001166114.2(PNPLA6):c.3361del (p.Leu1121fs)	Pathogenic
156538	NM_001166114.2(PNPLA6):c.1243dup (p.Asp415fs)	Pathogenic
1801949	NM_001166114.2(PNPLA6):c.2089C>T (p.Gln697Ter)	Pathogenic
183693	NM_001166114.2(PNPLA6):c.3266G>A (p.Arg1089Gln)	Pathogenic
183694	NM_001166114.2(PNPLA6):c.2149G>C (p.Gly717Arg)	Pathogenic
1913453	NM_001166114.2(PNPLA6):c.1751del (p.Ile584fs)	Pathogenic
1975411	NM_001166114.2(PNPLA6):c.3851T>A (p.Leu1284Ter)	Pathogenic
2064887	NM_001166114.2(PNPLA6):c.1968C>A (p.Cys656Ter)	Pathogenic
2099423	NM_001166114.2(PNPLA6):c.811C>T (p.Gln271Ter)	Pathogenic

SpliceAI

5245 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7536021:G:GG	donor_gain	1.0000
19:7536444:CCCAG:C	acceptor_loss	1.0000
19:7536446:CAG:C	acceptor_loss	1.0000
19:7536447:AGGTG:A	acceptor_loss	1.0000
19:7536448:G:A	acceptor_loss	1.0000
19:7536448:GGT:G	acceptor_gain	1.0000
19:7536514:G:GT	donor_gain	1.0000
19:7536542:AAGAA:A	donor_gain	1.0000
19:7536543:AGAA:A	donor_gain	1.0000
19:7536544:G:GT	donor_gain	1.0000
19:7536544:GAA:G	donor_gain	1.0000
19:7536545:AA:A	donor_gain	1.0000
19:7536547:G:GA	donor_loss	1.0000
19:7536547:G:GG	donor_gain	1.0000
19:7536548:T:A	donor_loss	1.0000
19:7536552:G:GT	donor_gain	1.0000
19:7539913:A:AG	acceptor_gain	1.0000
19:7539913:ACCAG:A	acceptor_gain	1.0000
19:7539914:CCAGG:C	acceptor_loss	1.0000
19:7539915:CAGG:C	acceptor_loss	1.0000
19:7539916:A:AG	acceptor_gain	1.0000
19:7539916:A:G	acceptor_loss	1.0000
19:7539916:AG:A	acceptor_gain	1.0000
19:7539917:G:GA	acceptor_gain	1.0000
19:7539917:G:GT	acceptor_gain	1.0000
19:7539917:GG:G	acceptor_gain	1.0000
19:7539917:GGA:G	acceptor_gain	1.0000
19:7539917:GGAT:G	acceptor_gain	1.0000
19:7539917:GGATC:G	acceptor_gain	1.0000
19:7540030:G:GT	donor_gain	1.0000

AlphaMissense

8783 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:7536223:T:C	F98L	1.000
19:7536224:T:C	F98S	1.000
19:7536225:C:A	F98L	1.000
19:7536225:C:G	F98L	1.000
19:7536236:A:T	D102V	1.000
19:7536254:G:A	G108D	1.000
19:7536540:C:A	A145D	1.000
19:7540046:T:C	L190P	1.000
19:7541412:T:C	L337P	1.000
19:7550395:T:A	W647R	1.000
19:7550395:T:C	W647R	1.000
19:7550557:G:A	G672R	1.000
19:7550557:G:C	G672R	1.000
19:7550557:G:T	G672W	1.000
19:7550558:G:A	G672E	1.000
19:7550558:G:T	G672V	1.000
19:7550564:T:C	L674P	1.000
19:7550635:G:C	G698R	1.000
19:7551037:C:A	A714E	1.000
19:7551055:T:C	L720P	1.000
19:7551375:T:C	L742P	1.000
19:7553992:T:C	L803P	1.000
19:7554646:T:A	W863R	1.000
19:7554646:T:C	W863R	1.000
19:7554989:T:A	W921R	1.000
19:7554989:T:C	W921R	1.000
19:7556516:G:T	G1063W	1.000
19:7557194:A:C	S1113R	1.000
19:7557196:C:A	S1113R	1.000
19:7557196:C:G	S1113R	1.000

dbSNP variants (sampled 300 via entrez): RS1000008449 (19:7560692 C>G,T), RS1000024240 (19:7539365 G>T), RS1000046657 (19:7542497 G>A), RS1000099923 (19:7555751 G>A), RS1000113905 (19:7537121 A>G), RS1000424459 (19:7543375 C>T), RS1000455456 (19:7543592 A>G), RS1000549473 (19:7536650 C>G,T), RS1000636476 (19:7538075 T>A), RS1000720258 (19:7532885 G>A), RS1000725564 (19:7549772 C>G,T), RS1000765552 (19:7545561 A>G), RS1000966065 (19:7537888 C>A), RS1001046849 (19:7559763 G>A), RS1001173506 (19:7554592 C>G)

Disease associations

OMIM: gene MIM:603197 | disease phenotypes: MIM:612020, MIM:245800, MIM:215470, MIM:275400, MIM:108600, MIM:303350, MIM:212840, MIM:146110

GenCC curated gene-disease

Disease	Classification	Inheritance
retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome	Definitive	Autosomal recessive
hereditary spastic paraplegia 39	Strong	Autosomal recessive
cerebellar ataxia-hypogonadism syndrome	Supportive	Autosomal recessive
ataxia-hypogonadism-choroidal dystrophy syndrome	Supportive	Autosomal recessive
Laurence-Moon syndrome	Supportive	Autosomal recessive
trichomegaly-retina pigmentary degeneration-dwarfism syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome	Definitive	AR
PNPLA6-related spastic paraplegia with or without ataxia	Definitive	AR

Mondo (19): hereditary spastic paraplegia 39 (MONDO:0012787), Laurence-Moon syndrome (MONDO:0009514), ataxia-hypogonadism-choroidal dystrophy syndrome (MONDO:0008980), trichomegaly-retina pigmentary degeneration-dwarfism syndrome (MONDO:0010152), spastic ataxia (MONDO:0017845), hereditary spastic paraplegia (MONDO:0019064), peripheral precocious puberty (MONDO:0015791), Kallmann syndrome (MONDO:0018800), inherited retinal dystrophy (MONDO:0019118), cerebellar ataxia-hypogonadism syndrome (MONDO:0008935), optic atrophy (MONDO:0003608), cerebellar ataxia (MONDO:0000437), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), PNPLA6-related spastic paraplegia with or without ataxia (MONDO:0100149), peripheral neuropathy (MONDO:0005244)

Orphanet (13): Autosomal recessive spastic paraplegia type 39 (Orphanet:139480), Laurence-Moon syndrome (Orphanet:2377), Ataxia-hypogonadism-choroidal dystrophy syndrome (Orphanet:1180), Trichomegaly-retina pigmentary degeneration-dwarfism syndrome (Orphanet:3363), Spastic ataxia (Orphanet:316226), Hereditary spastic paraplegia (Orphanet:685), Rare peripheral precocious puberty (Orphanet:178040), Kallmann syndrome (Orphanet:478), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cerebellar ataxia-hypogonadism syndrome (Orphanet:1173), Rare ataxia (Orphanet:102002), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

116 total (30 of 116 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000083	Renal insufficiency
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000529	Progressive visual loss
HP:0000533	Chorioretinal atrophy
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000556	Retinal dystrophy
HP:0000580	Pigmentary retinopathy
HP:0000612	Iris coloboma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000726	Dementia

GWAS associations

0 associations (top):

MeSH disease descriptors (15)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
D007849	Laurence-Moon Syndrome	C10.228.140.617.500; C16.131.077.509
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C565870	Cerebellar Ataxia and Hypogonadotropic Hypogonadism (supp.)
C565850	Chorioretinal Dystrophy, Spinocerebellar Ataxia, and Hypogonadotropic Hypogonadism (supp.)
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)
C536554	Oliver-McFarlane syndrome (supp.)
C564815	Spastic Ataxia (supp.)
C567433	Spastic Paraplegia 39, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189129 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

66 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
mipafox	decreases reaction, increases hydrolysis, decreases activity, affects response to substance	6
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	decreases response to substance, decreases activity, affects response to substance	4
methamidophos	decreases activity, increases phosphorylation	3
Isoflurophate	decreases activity, affects response to substance	3
Cadmium Chloride	increases expression	3
arsenite	increases methylation, affects binding, decreases reaction	2
phenyl valerate	increases hydrolysis, decreases hydrolysis, increases chemical synthesis, decreases reaction	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide	decreases activity	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
9-(tetrahydro-2-furyl)-adenine	decreases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
phenylsaligenin cyclic phosphate	decreases activity	1
di-n-butyl-2,2-dichlorovinyl phosphate	decreases activity	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases expression	1
CD 437	decreases expression	1
malaoxon	decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2209083	Binding	Inhibition of PNPLA6 binding to FP-biotin in [12C][14N]-lysine, arginine and [13C6][15N2]-lysine, arginine labeled HEK293T cells at 20 uM after 1 hr by isotopic activity-based protein profiling-MudPIT assay	Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. — J Med Chem

Clinical trials (associated diseases)

127 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00064987	PHASE2	TERMINATED	Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00392756	PHASE1	COMPLETED	Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)
NCT00493961	PHASE1	COMPLETED	Studying the Effects of 7 Days of Gonadotropin Releasing Hormone (GnRH) Treatment in Men With Hypogonadism
NCT00914823	PHASE1	COMPLETED	Kisspeptin Administration in the Adult
NCT01438034	PHASE1	COMPLETED	Kisspeptin in the Evaluation of Delayed Puberty
NCT03118479	PHASE1	TERMINATED	Effect of Varying Testosterone Levels on Insulin Sensitivity in Men With Idiopathic Hypogonadotropic Hypogonadism (IHH)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)