BSCL2

Summary

BSCL2 (BSCL2 lipid droplet biogenesis associated, seipin, HGNC:15832) is a protein-coding gene on chromosome 11q12.3, encoding Seipin (Q96G97). Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.

This gene encodes the multi-pass transmembrane protein seipin. This protein localizes to the endoplasmic reticulum and may be important for lipid droplet morphology. Mutations in this gene have been associated with congenital generalized lipodystrophy type 2 or Berardinelli-Seip syndrome, a rare autosomal recessive disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Naturally occurring read-through transcription occurs between this locus and the neighboring locus HNRNPUL2 (heterogeneous nuclear ribonucleoprotein U-like 2).

Source: NCBI Gene 26580 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal hereditary motor neuropathy (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 597 total — 32 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 122
• MANE Select transcript: NM_001122955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15832
Approved symbol	BSCL2
Name	BSCL2 lipid droplet biogenesis associated, seipin
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	seipin
Ensembl gene	ENSG00000168000
Ensembl biotype	protein_coding
OMIM	606158
Entrez	26580

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 37 protein_coding, 16 retained_intron, 6 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000278893, ENST00000301781, ENST00000360796, ENST00000403098, ENST00000403550, ENST00000405837, ENST00000407022, ENST00000412351, ENST00000413908, ENST00000421906, ENST00000448568, ENST00000449636, ENST00000463679, ENST00000464544, ENST00000468505, ENST00000470529, ENST00000524862, ENST00000526426, ENST00000528874, ENST00000530009, ENST00000530900, ENST00000531524, ENST00000532115, ENST00000532818, ENST00000533982, ENST00000537604, ENST00000679883, ENST00000682003, ENST00000682223, ENST00000682262, ENST00000682555, ENST00000682644, ENST00000682794, ENST00000683025, ENST00000683193, ENST00000683296, ENST00000683368, ENST00000683494, ENST00000683846, ENST00000683892, ENST00000684067, ENST00000684115, ENST00000684258, ENST00000684285, ENST00000684475, ENST00000684609, ENST00000684720, ENST00000854115, ENST00000854116, ENST00000854117, ENST00000854118, ENST00000854119, ENST00000854120, ENST00000912244, ENST00000912245, ENST00000912246, ENST00000912247, ENST00000912248, ENST00000912249, ENST00000951455, ENST00000951456, ENST00000951457, ENST00000951458

RefSeq mRNA: 5 — MANE Select: NM_001122955 NM_001122955, NM_001130702, NM_001386027, NM_001386028, NM_032667

CCDS: CCDS44627, CCDS55769, CCDS8031, CCDS91493

Canonical transcript exons

ENST00000360796 — 11 exons

Exon	Start	End
ENSE00001942351	62707109	62707424
ENSE00003491351	62705301	62705617
ENSE00003493349	62691280	62691421
ENSE00003494622	62690612	62690692
ENSE00003496627	62694568	62694711
ENSE00003507554	62691075	62691141
ENSE00003517566	62690275	62690521
ENSE00003522349	62690787	62690867
ENSE00003633789	62702468	62702549
ENSE00003656439	62692663	62692797
ENSE00003786836	62692376	62692473

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 66.5929 / max 660.4188, expressed in 1819 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120204	25.9405	1807
120215	13.0809	1692
120207	11.5169	318
120205	9.3060	1764
120208	3.1677	281
120212	1.6375	188
120206	0.4284	159
120211	0.3762	100
120201	0.2114	90
120213	0.1949	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superior frontal gyrus	UBERON:0002661	99.51	gold quality
primary visual cortex	UBERON:0002436	99.50	gold quality
pituitary gland	UBERON:0000007	99.43	gold quality
adenohypophysis	UBERON:0002196	99.43	gold quality
right testis	UBERON:0004534	99.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.35	gold quality
left testis	UBERON:0004533	99.32	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.29	gold quality
caudate nucleus	UBERON:0001873	99.27	gold quality
hypothalamus	UBERON:0001898	99.27	gold quality
right frontal lobe	UBERON:0002810	99.22	gold quality
frontal cortex	UBERON:0001870	99.21	gold quality
frontal lobe	UBERON:0016525	99.21	gold quality
prefrontal cortex	UBERON:0000451	99.19	gold quality
putamen	UBERON:0001874	99.16	gold quality
anterior cingulate cortex	UBERON:0009835	99.14	gold quality
cerebellum	UBERON:0002037	99.13	gold quality
cerebellar cortex	UBERON:0002129	99.13	gold quality
cerebellar hemisphere	UBERON:0002245	99.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.13	gold quality
cerebral cortex	UBERON:0000956	99.10	gold quality
brain	UBERON:0000955	99.05	gold quality
telencephalon	UBERON:0001893	99.03	gold quality
temporal lobe	UBERON:0001871	98.97	gold quality
amygdala	UBERON:0001876	98.96	gold quality
Ammon’s horn	UBERON:0001954	98.93	gold quality
testis	UBERON:0000473	98.69	gold quality
substantia nigra	UBERON:0002038	98.32	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.52
E-HCAD-25	yes	10.02
E-HCAD-5	no	9.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting BSCL2, 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-1252-5P	100.00	69.80	2774
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-6730-3P	97.03	67.54	889

Literature-anchored findings (GeneRIF, showing 40)

• Alterations in BSCL2 (seipin gene) are responsible for BSCL (OMIM :606158).Predicted human seipin protein sequence. (PMID:11479539)
• Congenital lipodystrophy patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene. (PMID:14602785)
• Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. (PMID:14981520)
• seipin is an integral membrane protein of the endoplasmic reticulum (ER) (PMID:14981520)
• We identified a novel nonsense mutation of seipin at codon 275 (R275X). Of four congenital generalized lipodystrophy patients, three were homozygous for R275X. No seipin mutation was found in any exon in one patient. (PMID:15126564)
• mutations in AGPAT2 and Gng3lg are approximately equally represented in congenital generalized lipodystrophy (PMID:15181077)
• Our study indicates that the dominant N88S mutation in the Berardinelli-Seip congenital lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders. (PMID:15732094)
• description of two Dutch families with BSCL2 mutations and phenotypic variability of the gene mutation. Features are compatible with Silver syndrome, variant Silver syndrome (foot rather than hand involvement), distal HMN type II, or distal HMN type V. (PMID:16427281)
• mutations in AGPAT2 or Seipin may have roles in Berardinelli-Seip congenital lipodystrophy (PMID:16435205)
• This study reaffirms the clinical phenotype of the disorders associated with a BSCL2 Ser90Leu mutation and describes a genetically proven family with Silver syndrome and dHMN type V in Asia. (PMID:17486577)
• The 669insA mutation in exon 4 of the BSCL2 gene was identified as the major genetic alteration leading to BSCL in a group of 22 patients from the northeastern Brazilian state of Rio Grande do Norte. (PMID:17535271)
• Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. (PMID:17663003)
• seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology (PMID:18093937)
• Berardinelli-Seip syndrome is a congenital form of generalized lipodystrophy, transmitted as an autosomal recessive trait. It is well documented in medicine and skin. It is a rare disorder caused by mutations of AGPAT2 gene or BSCL2 gene. (PMID:18155601)
• Silver syndrome–related to the N88S mutation in the BSCL2 gene–is characterized by a spectrum of clinical findings (PMID:18224579)
• These results suggest that an evolutionally conserved function of seipin in phospholipid metabolism and LD formation may be functionally important in human adipogenesis. (PMID:18250201)
• Study demonstrates that BSCL2 is an essential, cell-autonomous regulator of adipogenesis. (PMID:18458148)
• The transmembrane domains in seipin are critical for ER retention, ubiquitination, formation of inclusions, and activation of UPR. Seipin expression is detected in neurons in the spinal cord and in the frontal lobe cortex of the brain. (PMID:18585921)
• Here we report the third Italian family with dHMN and SPG17 in which two affected members harbor the heterozygous N88S mutation in the BSCL2 gene. (PMID:18612770)
• Case Report: novel BSCL2 mutation in an Indian patient with congenital generalized lipodystrophy associated with normal intellectual ability. (PMID:18690553)
• A new subtype of congenital generalized lipodystrophy is not associated with the BSCL2 gene. (PMID:18698612)
• BSCL2 gene mutations were found in the homozygous form in four Brazilian kindreds (c.412C>T c.464T>C, c.518-519insA, IVS5-2A>G), and in two kindreds compound mutations were found (c.1363C>T, c.424A>G). (PMID:19226263)
• We describe results of Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes. (PMID:19252810)
• Study showed that alterations in the pattern of lipid droplets in seipin deficient cells. (PMID:19278620)
• This report suggests that a different type of distal hereditary motor neuropathy could exist within one family carrying N88S mutations in BSCL2. (PMID:19323790)
• These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype. (PMID:19396477)
• Japanese CGL patients with BSCL2 mutations presented with severe insulin resistance, even during infancy, prior to the development of diabetes mellitus (PMID:19438831)
• Bscl2 is required for PPARgamma’s full activation to initiate the adipogenesis transcription program. (PMID:19574402)
• heterozygous mutation in the seipin gene in congenital lipodystrophy was associated with dystonia, mental retardation and behaviour change. (PMID:19762912)
• DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients with distal hereditary motor neuropathy type V (PMID:20598714)
• study of an Italian family with a Charcot-Marie-Tooth disease type 2 phenotype with pyramidal signs; in the 3 affected siblings an S90L mutation was revealed; confirms variability of phenotypes associated with Ser90Leu mutation (PMID:20806400)
• N88S seipin mutant transgenic mice develop motor neuron disease via endoplasmic reticulum stress. (PMID:21750110)
• the biochemical characteristics of seipin and its mis-sense mutants (PMID:21957196)
• the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets (PMID:22234369)
• This study showed that a A novel polymorphism G–>T was found in the Berardinelli-Seip congenital lipodystrophy 2 gene on intron 4 in patient with hereditary motor neuropathy type V in Italy family. (PMID:22427291)
• role of seipin in human disease (PMID:22474068)
• This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation. (PMID:23142943)
• The mutant seipin (Bscl2) formed protein aggregates in the CNS neurons of transgenic mice and caused a specific loss of alpha motor neurons in the ventral horn of spinal cord. (PMID:23470542)
• Identification of a known BSCL2 mutation in a family with Charcot-Marie-Tooth disease. (PMID:23553728)
• Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia. (PMID:23564749)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	bscl2l	ENSDARG00000025912
danio_rerio	bscl2	ENSDARG00000037008
mus_musculus	Bscl2	ENSMUSG00000071657
rattus_norvegicus	Bscl2	ENSRNOG00000052393
drosophila_melanogaster	Seipin	FBGN0040336
caenorhabditis_elegans		WBGENE00019808

Protein

Protein identifiers

Seipin — Q96G97 (reviewed: Q96G97)

Alternative names: Bernardinelli-Seip congenital lipodystrophy type 2 protein

All UniProt accessions (23): A0A024R549, A0A804HHX0, A0A804HIE2, A0A804HIJ7, A0A804HJB1, A0A804HJW1, A0A804HK11, A0A804HK83, A0A804HKZ9, E9PIU3, E9PJK0, E9PJS9, E9PPN5, E9PR78, E9PRU2, E9PSB5, Q96G97, F8W7Q8, F8WER0, H7BXM1, H7BYY0, H7C2D5, J3KQ12

UniProt curated annotations — full annotation on UniProt →

Function. Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis. In association with LDAF1, defines the sites of LD formation in the ER. Also required for growth and maturation of small nascent LDs into larger mature LDs. Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts, facilitating protein and lipid delivery from the ER into growing LDs. Regulates the maturation of ZFYVE1-positive nascent LDs and the function of the RAB18-ZFYVE1 complex in mediating the formation of ER-LD contacts. Binds anionic phospholipids including phosphatidic acid. Plays an important role in the differentiation and development of adipocytes.

Subunit / interactions. Undecamer (an oligomer having eleven subunits). Oligomerization is important for its function in lipid droplet formation. Interacts with LDAF1 to form an oligomeric complex. Interacts with RAB18. Interacts with ZFYVE1 in a RAB18-dependent manner. Interacts with LDAF1 to form an oligomeric complex.

Subcellular location. Endoplasmic reticulum membrane. Lipid droplet.

Tissue specificity. Expressed in motor neurons in the spinal cord and cortical neurons in the frontal lobe (at protein level). Highly expressed in brain, testis and adipose tissue.

Disease relevance. Lipodystrophy, congenital generalized, 2 (CGL2) [MIM:269700] A form of congenital generalized lipodystrophy, a metabolic disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 17, autosomal dominant (SPG17) [MIM:270685] 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. SPG17 is characterized by prominent amyotrophy of the hand muscles, the presence of mild to severe pyramidal tract signs and spastic paraplegia. SPG17 is a motor neuron disease overlapping with distal spinal muscular atrophy type 5. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal dominant 13 (HMND13) [MIM:619112] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. HMND13 is characterized by distal muscular atrophy primarily affecting the upper limbs. Lower limb involvement may occur at the same time or later. Clinical features are highly variable even within families, and include poor fine hand motor skills, difficulty walking, foot deformities, spasticity and hyperreflexia. Some HMND13 patients show axonal peripheral neuropathy and distal sensory impairment. HMND13 inheritance is autosomal dominant with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Encephalopathy, progressive, with or without lipodystrophy (PELD) [MIM:615924] A neurodegenerative disease characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade, hyperactive behavior, seizures, tremor and ataxic gait. Patients may show a mild or typical lipodystrophic appearance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the seipin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96G97-2	1	yes
Q96G97-3	2
Q96G97-4	3

RefSeq proteins (5): NP_001116427, NP_001124174, NP_001372956, NP_001372957, NP_116056 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009617	Seipin	Family

Pfam: PF06775

UniProt features (25 total): mutagenesis site 6, modified residue 4, topological domain 3, splice variant 3, sequence variant 3, glycosylation site 2, transmembrane region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6DS5	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96G97-F1	75.09	0.46

Functional residue map

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

Post-translational modifications (4): 372, 289, 346, 351

Glycosylation sites (2): 88, 242

Mutagenesis-validated functional residues (6):

Position	Phenotype
67	loss of oligomerization and function in lipid droplet formation; when associated with a-70; a-151; d-156; d-169 and a-17
70	loss of oligomerization and function in lipid droplet formation; when associated with r-67; a-151; d-156; d-169 and a-17
151	loss of oligomerization and function in lipid droplet biogenesis; when associated with r-67; a-70; d-156; d-169 and a-17
156	loss of oligomerization and function in lipid droplet formation; when associated with r-67; a-70; a-151; d-169 and a-175
169	loss of oligomerization and function in lipid droplet formation; when associated with r-67; a-70; a-151; d-156 and a-175
175	loss of oligomerization and function in lipid droplet formation; when associated with r-67; a-70; a-151; d-156 and d-169

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 442 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, AP4_Q6, CAGCTG_AP4_Q5, BROWNE_HCMV_INFECTION_48HR_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, ACATTCC_MIR1_MIR206, GOBP_ORGANELLE_ASSEMBLY, TGACATY_UNKNOWN, GOBP_LIPID_METABOLIC_PROCESS, GOBP_FAT_CELL_DIFFERENTIATION, MYB_Q3

GO Biological Process (8): lipid catabolic process (GO:0016042), lipid storage (GO:0019915), lipid droplet organization (GO:0034389), fat cell differentiation (GO:0045444), negative regulation of lipid catabolic process (GO:0050995), positive regulation of cold-induced thermogenesis (GO:0120162), lipid droplet formation (GO:0140042), lipid metabolic process (GO:0006629)

GO Molecular Function (2): phospholipid binding (GO:0005543), protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	1
catabolic process	1
nutrient storage	1
organelle organization	1
cell differentiation	1
negative regulation of catabolic process	1
lipid catabolic process	1
negative regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
lipid storage	1
lipid droplet organization	1
membraneless organelle assembly	1
primary metabolic process	1
lipid binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BSCL2	AGPAT2	O15120	988
BSCL2	CAVIN1	Q6NZI2	858
BSCL2	LDAF1	Q96B96	851
BSCL2	CAV1	Q03135	843
BSCL2	LMNA	P02545	803
BSCL2	ZMPSTE24	O75844	802
BSCL2	GARS1	P41250	768
BSCL2	GPAT4	Q86UL3	768
BSCL2	CA10	Q9NS85	762
BSCL2	REEP1	Q9H902	744
BSCL2	FITM2	Q8N6M3	731
BSCL2	SPART	Q8N0X7	716
BSCL2	LPIN1	Q14693	713
BSCL2	RAB18	Q9NP72	703
BSCL2	SPAST	Q9UBP0	697

IntAct

77 interactions, top by confidence:

A	B	Type	Score
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
TMEM19	BSCL2	psi-mi:“MI:0915”(physical association)	0.670
SMIM3	BSCL2	psi-mi:“MI:0915”(physical association)	0.670
BSCL2	TMEM19	psi-mi:“MI:0915”(physical association)	0.670
BSCL2	SMIM3	psi-mi:“MI:0915”(physical association)	0.670
BSCL2	USE1	psi-mi:“MI:0915”(physical association)	0.550
TSPAN17	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SYP	APBB1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
GABRG2	GPAA1	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
GABRE	FZD6	psi-mi:“MI:0914”(association)	0.530
TSPAN5	SC5D	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
HAS3	BSCL2	psi-mi:“MI:0915”(physical association)	0.400
BSCL2	BSCL2	psi-mi:“MI:0915”(physical association)	0.370
BSCL2	Hoxa1	psi-mi:“MI:0915”(physical association)	0.370
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350

BioGRID (254): NSG1 (Two-hybrid), TMEM19 (Two-hybrid), PLEKHF2 (Two-hybrid), SMIM3 (Two-hybrid), SMLR1 (Two-hybrid), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), BSCL2 (Affinity Capture-MS), KIAA2013 (Affinity Capture-MS), HDGFRP3 (Affinity Capture-MS), DNAJC13 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A2AWP8, A2RRU4, A2SXS5, A4D2P6, A6QM06, D4A6L0, E1BBQ2, E9Q6C8, F1LQY6, O00255, O88559, O94827, P29590, P56726, P97260, P97698, Q0GA42, Q0P5I0, Q0VF94, Q12770, Q17RQ9, Q29RM4, Q49LS8, Q5GH57, Q5GH73, Q5MNU5, Q5SNT2, Q5T848, Q69Z89, Q6DVA0, Q6GQT6, Q6IEE7, Q70EL4, Q8BUM9, Q8C190, Q8C419, Q8NC56, Q8TCT7, Q91ZP9

Diamond homologs: F4I340, Q5E9P6, Q5FVJ6, Q8L615, Q96G97, Q9FFD9, Q9Z2E9, Q9V3X4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Neurotransmitter receptors and postsynaptic signal transmission	7	12.3×	5e-04
Transmission across Chemical Synapses	7	9.3×	2e-03
Neuronal System	8	6.2×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	6	17.1×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	15
Uncertain significance	301
Likely benign	168
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076721	NM_001122955.4(BSCL2):c.1113del (p.Thr372fs)	Pathogenic
1359323	NM_001122955.4(BSCL2):c.1159C>T (p.Gln387Ter)	Pathogenic
143858	NM_001122955.4(BSCL2):c.985C>T (p.Arg329Ter)	Pathogenic
2135166	NM_001122955.4(BSCL2):c.567_568insGGCATGGACCCCAGTAACACCACCTAAATAGCAGCCCTAATCATCGCCAATTCTTCTCGTTCGGGAGGTGAGGTTGTCGACTGCAGAGAGTCGATCACGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGATTTGGGCATG (p.Phe190delinsGlyMetAspProSerAsnThrThrTer)	Pathogenic
2427057	NC_000011.9:g.(?62457839)(62462203_?)del	Pathogenic
2664673	NM_001122955.4(BSCL2):c.591C>A (p.Tyr197Ter)	Pathogenic
2743145	NM_001122955.4(BSCL2):c.567_568insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGATTTGGGCATG (p.Phe190delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerTer)	Pathogenic
2894477	NM_001122955.4(BSCL2):c.1024_1025del (p.Asp342fs)	Pathogenic
3244692	NC_000011.9:g.(?62457839)(62472984_?)del	Pathogenic
3648946	NM_001122955.4(BSCL2):c.553C>T (p.Gln185Ter)	Pathogenic
3658282	NM_001122955.4(BSCL2):c.963G>A (p.Trp321Ter)	Pathogenic
372117	NM_001122955.4(BSCL2):c.766-2A>G	Pathogenic
372120	NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)	Pathogenic
434545	NM_001122955.4(BSCL2):c.942dup (p.Leu315fs)	Pathogenic
4532	NM_001122955.4(BSCL2):c.493_494insAA (p.Met165fs)	Pathogenic
4532106	NM_001122955.4(BSCL2):c.630+1G>T	Pathogenic
4534	BSCL2, 258-BP DEL/12-BP INS	Pathogenic
4536	NM_001122955.4(BSCL2):c.517dup (p.Thr173fs)	Pathogenic
4537	NM_001122955.4(BSCL2):c.604C>T (p.Arg202Ter)	Pathogenic
4540	NM_001122955.4(BSCL2):c.828del (p.Tyr277fs)	Pathogenic
4543	NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)	Pathogenic
4545	NM_001122955.4(BSCL2):c.1015C>T (p.Arg339Ter)	Pathogenic
4546	NM_001122955.4(BSCL2):c.757G>T (p.Glu253Ter)	Pathogenic
4687517	NM_001122955.4(BSCL2):c.324_325del (p.Ser109fs)	Pathogenic
4729018	NM_001122955.4(BSCL2):c.1026_1027del (p.Asp342fs)	Pathogenic
476810	NM_001122955.4(BSCL2):c.461C>G (p.Ser154Trp)	Pathogenic
476817	NM_001122955.4(BSCL2):c.1108_1109del (p.Asp370fs)	Pathogenic
543298	NC_000011.10:g.(?62702448)(62702569_?)del	Pathogenic
549713	NM_001122955.4(BSCL2):c.404+1G>T	Pathogenic
549714	NM_001122955.4(BSCL2):c.759_760del (p.Asn254fs)	Pathogenic

SpliceAI

2407 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62690689:CCCT:C	acceptor_gain	1.0000
11:62690690:CCTC:C	acceptor_gain	1.0000
11:62690691:CT:C	acceptor_gain	1.0000
11:62690693:C:CC	acceptor_gain	1.0000
11:62690700:C:CT	acceptor_gain	1.0000
11:62690700:C:T	acceptor_gain	1.0000
11:62690701:A:T	acceptor_gain	1.0000
11:62690783:ATAC:A	donor_loss	1.0000
11:62690785:A:C	donor_loss	1.0000
11:62690786:C:A	donor_loss	1.0000
11:62690786:CC:C	donor_loss	1.0000
11:62690866:CC:C	acceptor_gain	1.0000
11:62690867:CC:C	acceptor_gain	1.0000
11:62690868:C:CC	acceptor_gain	1.0000
11:62690868:C:CG	acceptor_loss	1.0000
11:62690874:C:T	acceptor_gain	1.0000
11:62690877:C:CT	acceptor_gain	1.0000
11:62690877:C:T	acceptor_gain	1.0000
11:62690878:A:T	acceptor_gain	1.0000
11:62691070:TTTAC:T	donor_loss	1.0000
11:62691071:TTAC:T	donor_loss	1.0000
11:62691074:CCTGG:C	donor_gain	1.0000
11:62691137:TTAAC:T	acceptor_gain	1.0000
11:62691138:TAAC:T	acceptor_gain	1.0000
11:62691139:AAC:A	acceptor_gain	1.0000
11:62691140:AC:A	acceptor_gain	1.0000
11:62691141:CC:C	acceptor_gain	1.0000
11:62691142:C:CC	acceptor_gain	1.0000
11:62691324:A:AC	donor_gain	1.0000
11:62691325:C:CC	donor_gain	1.0000

AlphaMissense

2967 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62691370:G:C	S241R	0.999
11:62691370:G:T	S241R	0.999
11:62691372:T:G	S241R	0.999
11:62694665:A:G	L114P	0.999
11:62694671:A:G	L112P	0.999
11:62691352:G:C	S247R	0.998
11:62691352:G:T	S247R	0.998
11:62691354:T:G	S247R	0.998
11:62694623:A:T	V128D	0.998
11:62694646:A:C	N120K	0.998
11:62694646:A:T	N120K	0.998
11:62702503:C:G	A87P	0.998
11:62705386:A:G	W43R	0.998
11:62705386:A:T	W43R	0.998
11:62691334:G:C	S253R	0.997
11:62691334:G:T	S253R	0.997
11:62691336:T:G	S253R	0.997
11:62691380:C:T	G238D	0.997
11:62692406:A:G	L214P	0.997
11:62694657:A:G	S117P	0.997
11:62705364:C:T	G50D	0.997
11:62691381:C:G	G238R	0.996
11:62692448:A:T	I200N	0.996
11:62694671:A:T	L112H	0.996
11:62694690:A:C	Y106D	0.996
11:62691389:G:T	A235D	0.995
11:62692388:A:G	F220S	0.995
11:62694572:C:G	R145P	0.995
11:62694662:G:T	P115Q	0.995
11:62694690:A:G	Y106H	0.995

dbSNP variants (sampled 300 via entrez): RS1000032668 (11:62699829 C>A), RS1000220072 (11:62708143 G>A,C,T), RS1000405104 (11:62710854 G>A,C,T), RS1000490378 (11:62695359 T>C), RS1000536287 (11:62690867 C>G,T), RS1001070714 (11:62700861 G>A,C), RS1001126910 (11:62706647 G>A,C), RS1001197467 (11:62700159 T>C), RS1001231514 (11:62699899 G>A), RS1001313790 (11:62706416 T>C), RS1001438743 (11:62701093 A>G), RS1001519786 (11:62705100 G>A), RS1001727657 (11:62711448 T>C), RS1001757286 (11:62711275 G>A), RS1001777289 (11:62694401 C>T)

Disease associations

OMIM: gene MIM:606158 | disease phenotypes: MIM:269700, MIM:270685, MIM:615924, MIM:303350, MIM:619112, MIM:600794, MIM:604367, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital generalized lipodystrophy type 2	Definitive	Autosomal recessive
severe neurodegenerative syndrome with lipodystrophy	Strong	Autosomal recessive
neonatal diabetes mellitus	Strong	Autosomal recessive
generalized lipodystrophy	Strong	Autosomal recessive
hereditary spastic paraplegia 17	Strong	Autosomal dominant
neuronopathy, distal hereditary motor, type 5C	Strong	Autosomal dominant
lipodystrophy	Strong	Autosomal recessive
neuronopathy, distal hereditary motor, type 5A	Supportive	Autosomal dominant
Berardinelli-Seip congenital lipodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
distal hereditary motor neuropathy	Definitive	AD
lipodystrophy	Definitive	AR

Mondo (18): Charcot-Marie-Tooth disease type 2 (MONDO:0018993), congenital generalized lipodystrophy type 2 (MONDO:0010020), hereditary spastic paraplegia 17 (MONDO:0010043), severe neurodegenerative syndrome with lipodystrophy (MONDO:0014402), hereditary spastic paraplegia (MONDO:0019064), neuronopathy, distal hereditary motor, type 5C (MONDO:0030860), lipodystrophy (MONDO:0006573), neuronopathy, distal hereditary motor, type 5A (MONDO:0015353), Berardinelli-Seip congenital lipodystrophy (MONDO:0018883), monogenic diabetes (MONDO:0015967), young-onset Parkinson disease (MONDO:0017279), developmental and epileptic encephalopathy (MONDO:0100620), PPARG-related familial partial lipodystrophy (MONDO:0011448), intellectual disability (MONDO:0001071), peripheral neuropathy (MONDO:0005244)

Orphanet (12): Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Autosomal dominant spastic paraplegia type 17 (Orphanet:100998), Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome (Orphanet:363400), Congenital generalized lipodystrophy (Orphanet:528), Hereditary spastic paraplegia (Orphanet:685), Congenital generalized lipodystrophy type 2 (Orphanet:696289), Distal hereditary motor neuropathy type 5 (Orphanet:139536), Rare genetic diabetes mellitus (Orphanet:183625), Young-onset Parkinson disease (Orphanet:2828), PPARG-related familial partial lipodystrophy (Orphanet:79083), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000065	Labial hypertrophy
HP:0000098	Tall stature
HP:0000144	Decreased fertility
HP:0000147	Polycystic ovaries
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000325	Triangular face
HP:0000400	Macrotia
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000787	Nephrolithiasis
HP:0000822	Hypertension
HP:0000842	Hyperinsulinemia
HP:0000855	Insulin resistance
HP:0000868	Decreased fertility in females
HP:0000877	Insulin-resistant diabetes mellitus at puberty
HP:0000956	Acanthosis nigricans
HP:0001007	Hirsutism
HP:0001171	Split hand
HP:0001176	Large hands
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001268	Mental deterioration
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002363_1	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	6.000000e-06
GCST005956_12	Waist-to-hip ratio adjusted for BMI	2.000000e-06
GCST005956_2	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_37	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	5.000000e-07
GCST005962_51	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008060	Lipodystrophy	C17.800.849.391; C18.452.584.625; C18.452.880.391
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
C536644	Spastic paraplegia 17 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
methylmercuric chloride	increases expression	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Antimycin A	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	increases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Fonofos	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Parathion	increases methylation	1
Phthalic Acids	increases methylation	1
Quercetin	increases expression	1
Selenium	affects cotreatment, increases expression	1
Smoke	increases abundance, increases expression	1
Vitamin E	affects cotreatment, increases expression	1
Mifepristone	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04026178	PHASE4	COMPLETED	Immunogenicity of Metreleptin in Patients With Generalized Lipodystrophy
NCT00005764	PHASE4	COMPLETED	A Study of Increased Lactic Acid and Abnormal Fat Distribution in HIV-Positive Patients
NCT00006190	PHASE4	COMPLETED	A Study to Determine How and Why HIV-Infected Subjects on Anti-viral Treatment Develop Lipodystrophy
NCT00119769	PHASE4	COMPLETED	The Effect of Low-Dose Human Growth Hormone Therapy in HIV Infected Patients
NCT00192621	PHASE4	COMPLETED	Seronegatives and Metabolic Abnormalities Protocol 2 (SAMA002): Study to Compare the Effect of Kaletra and Combivir® in HIV-Negative Healthy Subjects
NCT00202228	PHASE4	COMPLETED	Lactate Metabolism Study in HIV Infected Persons
NCT00227500	PHASE4	COMPLETED	Pravastatin for Hyperlipidaemia in HIV.
NCT00360139	PHASE4	WITHDRAWN	Clinical Trial to Determine the Efficacy of Sculptra™ Dermal Filler for the Correction of Contour Deformities Caused by Lipoatrophy
NCT00426296	PHASE4	UNKNOWN	SHARE: Simple HAART With Abacavir, Reyataz, and Epivir
NCT00865007	PHASE4	COMPLETED	Lopinavir/r Monotherapy Versus Abacavir/Lamivudine and Lopinavir/r for Limb Fat Recovery in Persons With Lipoatrophy
NCT01612858	PHASE4	COMPLETED	Metabolic Abnormalities in HIV-infected Persons
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04113317	PHASE3	COMPLETED	Granulocyte-Colony Stimulating Factor (G-CSF) as Optimizing Therapy for Pediatric Liver Transplantation
NCT06502990	PHASE3	RECRUITING	Open-label Study to Evaluate Metreleptin in Children Under 6 Years of Age With Generalised Lipodystrophy
NCT06548100	PHASE3	ACTIVE_NOT_RECRUITING	A Study of the Safety of Mibavademab in Pediatric and Adult Participants Switching From Metreleptin to Mibavademab for the Treatment of Generalized Lipodystrophy (GLD)
NCT07220785	PHASE3	RECRUITING	Efficacy and Safety of Mibavademab in Adult and Pediatric Patients With Generalized Lipodystrophy
NCT00006412	PHASE3	COMPLETED	Safety and Effectiveness of Fenofibrate and Pravastatin in HIV-Positive Patients With Abnormal Blood Lipids
NCT00082628	PHASE3	COMPLETED	Treatment of Abnormal Adipose Tissue Accumulation in Human Immunodeficiency Virus (HIV) Patients
NCT00123253	PHASE3	COMPLETED	TH9507 in Patients With HIV-Associated Lipodystrophy
NCT00608023	PHASE3	COMPLETED	TH9507 Extension Study in Patients With HIV-Associated Lipodystrophy
NCT02262832	PHASE3	ACTIVE_NOT_RECRUITING	Compassionate Use of Metreleptin in Previously Treated People With Generalized Lipodystrophy
NCT04860063	PHASE3	UNKNOWN	Effect of Berberine on Metabolic Syndrome, Efficacy and Safety in Combination With Antiretroviral Therapy in PLWH.
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT04159415	PHASE2	COMPLETED	Study of REGN4461, a Leptin Receptor Agonist Antibody, in Patients With Generalized Lipodystrophy
NCT00005905	PHASE2	COMPLETED	Leptin to Treat Lipodystrophy
NCT00021463	PHASE2	COMPLETED	Changing to Nonprotease Inhibitor Treatment to Improve Side Effects
NCT00025883	PHASE2	COMPLETED	Leptin to Treat Lipodystrophy
NCT00119379	PHASE2	COMPLETED	Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults
NCT00461552	PHASE2	COMPLETED	Therapeutic Approaches to HAART-Induced Lipodystrophy
NCT00647946	PHASE2	COMPLETED	Study to Evaluate Changes in Limb Fat When Switching From a Thymidine Analogue
NCT00656175	PHASE2	COMPLETED	Raltegravir Therapy for Women With HIV and Fat Accumulation
NCT01679197	PHASE2	COMPLETED	Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy
NCT01778556	PHASE2	COMPLETED	Short-term Effects of Leptin in People With Lipodystrophy
NCT02262806	PHASE2	ACTIVE_NOT_RECRUITING	Compassionate Use of Metreleptin in Previously Treated People With Partial Lipodystrophy
NCT02639286	PHASE2	COMPLETED	Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension
NCT07313787	PHASE2	NOT_YET_RECRUITING	Effects of Meal Macronutrients on Postprandial Lipids
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia