Lysinuric protein intolerance

Summary

Lysinuric protein intolerance (MONDO:0009109) is a disease caused by SLC7A7 (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Italy) [Orphanet-validated]
• Causal gene: SLC7A7 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 817
• Phenotypes (HPO): 77
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1.7	Italy	Validated
Prevalence at birth	1-9 / 100 000	1.7	Finland	Validated
Prevalence at birth	1-9 / 100 000	1.75	Japan	Validated
Prevalence at birth	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

77 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0000091	Abnormal renal tubule morphology	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000099	Glomerulonephritis	Frequent (30-79%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0000124	Renal tubular dysfunction	Frequent (30-79%)
HP:0000790	Hematuria	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001394	Cirrhosis	Frequent (30-79%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002154	Hyperglycinemia	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002570	Steatorrhea	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0003141	Increased LDL cholesterol concentration	Frequent (30-79%)
HP:0003217	Hyperglutaminemia	Frequent (30-79%)
HP:0003233	Decreased HDL cholesterol concentration	Frequent (30-79%)
HP:0003268	Argininuria	Frequent (30-79%)
HP:0003297	Hyperlysinuria	Frequent (30-79%)
HP:0003348	Hyperalaninemia	Frequent (30-79%)
HP:0006517	Intraalveolar phospholipid accumulation	Frequent (30-79%)
HP:0006530	Abnormal pulmonary interstitial morphology	Frequent (30-79%)
HP:0008358	Hyperprolinemia	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011966	Elevated plasma citrulline	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012156	Hemophagocytosis	Frequent (30-79%)
HP:0012213	Decreased glomerular filtration rate	Frequent (30-79%)
HP:0012278	Abnormality of serine metabolism	Frequent (30-79%)
HP:0012523	Oral aversion	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0031020	Bone marrow hypercellularity	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000822	Hypertension	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lysinuric protein intolerance
Mondo ID	MONDO:0009109
MeSH	C562687
OMIM	222700
Orphanet	470
DOID	DOID:0060439
ICD-11	972050440
NCIT	C121563
SNOMED CT	303852004
UMLS	C0268647
MedGen	75704
GARD	0003335
MedDRA	10058300
Is cancer (heuristic)	no

Also known as: dibasic aminoaciduria 2 · Dibasicamino aciduria II · hyperdibasic aminoaciduria · hyperdibasic aminoaciduria type 2 · LPI · lysinuric protein intolerance

Data availability: 817 ClinVar variants · 4 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › lysinuric protein intolerance

Related subtypes (18): blue diaper syndrome, ocular cystinosis, juvenile nephropathic cystinosis, cystinuria, hyperdibasic aminoaciduria type 1, dicarboxylic aminoaciduria, Hartnup disease, histidinuria due to a renal tubular defect, iminoglycinuria, oculocerebrorenal syndrome, hypotonia-cystinuria syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, episodic ataxia type 6, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, disorder of neutral amino acid transport, autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome, nephropathic infantile cystinosis, undetermined early-onset epileptic encephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

296 likely benign, 164 uncertain significance, 44 likely pathogenic, 40 pathogenic, 21 pathogenic/likely pathogenic, 17 benign, 16 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453292	NM_003982.4(SLC7A7):c.88C>T (p.Gln30Ter)	LOC130055323	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1924991	NM_003982.4(SLC7A7):c.110dup (p.Ser38fs)	LOC130055323	Pathogenic	criteria provided, single submitter
2678979	NM_003982.4(SLC7A7):c.70del (p.Ala24fs)	LOC130055323	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994997	NM_003982.4(SLC7A7):c.3G>A (p.Met1Ile)	LOC130055324	Pathogenic	criteria provided, single submitter
2706171	NM_003982.4(SLC7A7):c.21T>A (p.Tyr7Ter)	LOC130055324	Pathogenic	criteria provided, single submitter
2901913	NM_003982.4(SLC7A7):c.2T>C (p.Met1Thr)	LOC130055324	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033295	NM_003982.4(SLC7A7):c.377del (p.Ile126fs)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067388	NM_003982.4(SLC7A7):c.770+1G>T	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068688	NM_003982.4(SLC7A7):c.426_434del (p.Tyr142_Gln145delinsTer)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069542	NM_003982.4(SLC7A7):c.293dup (p.Lys99fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1070579	NM_003982.4(SLC7A7):c.766G>T (p.Glu256Ter)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070969	NM_003982.4(SLC7A7):c.1263_1269del (p.Ile422fs)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071587	NM_003982.4(SLC7A7):c.1116C>G (p.Tyr372Ter)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071672	NC_000014.9:g.22774114_22774118del	SLC7A7	Pathogenic	criteria provided, single submitter
1075788	NM_003982.4(SLC7A7):c.889dup (p.Ala297fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1076198	NM_003982.4(SLC7A7):c.701del (p.Tyr233_Ser234insTer)	SLC7A7	Pathogenic	criteria provided, multiple submitters, no conflicts
1076350	NC_000014.8:g.(?23241431)(23290020_?)del	SLC7A7	Pathogenic	criteria provided, single submitter
1076351	NC_000014.8:g.(?23282099)(23285111_?)del	SLC7A7	Pathogenic	criteria provided, single submitter
1355862	NM_003982.4(SLC7A7):c.949del (p.Ala317fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1371202	NM_003982.4(SLC7A7):c.539del (p.Gly180fs)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376330	NM_003982.4(SLC7A7):c.126_129del (p.Val43fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1384004	NM_003982.4(SLC7A7):c.930G>A (p.Trp310Ter)	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391087	NM_003982.4(SLC7A7):c.625+1G>T	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1397899	NC_000014.8:g.(?23242819)(23282607_?)del	SLC7A7	Pathogenic	criteria provided, single submitter
1430248	NM_003982.4(SLC7A7):c.608_609del (p.Ile203fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1451547	NM_003982.4(SLC7A7):c.770+1del	SLC7A7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452476	NM_003982.4(SLC7A7):c.371del (p.Leu124fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1459477	NM_003982.4(SLC7A7):c.1400del (p.Lys467fs)	SLC7A7	Pathogenic	criteria provided, single submitter
1459832	NM_003982.4(SLC7A7):c.465T>G (p.Tyr155Ter)	SLC7A7	Pathogenic	criteria provided, single submitter
1460241	NM_003982.4(SLC7A7):c.635_638dup (p.Phe214fs)	SLC7A7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC7A7	Definitive	Autosomal recessive	lysinuric protein intolerance	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC7A7	Orphanet:470	Lysinuric protein intolerance
SPTA1	Orphanet:288	Hereditary elliptocytosis
SPTA1	Orphanet:822	Hereditary spherocytosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC7A7	HGNC:11065	ENSG00000155465	Q9UM01	Y+L amino acid transporter 1	gencc,clinvar
SPTA1	HGNC:11272	ENSG00000163554	P02549	Spectrin alpha chain, erythrocytic 1	clinvar
ACIN1	HGNC:17066	ENSG00000100813	Q9UKV3	Apoptotic chromatin condensation inducer in the nucleus	clinvar
OXA1L	HGNC:8526	ENSG00000155463	Q15070	Mitochondrial inner membrane protein OXA1L	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC7A7	Y+L amino acid transporter 1	Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide sy…
SPTA1	Spectrin alpha chain, erythrocytic 1	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
ACIN1	Apoptotic chromatin condensation inducer in the nucleus	Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs.
OXA1L	Mitochondrial inner membrane protein OXA1L	Mitochondrial membrane insertase that mediates the cotranslational insertion of integral membrane proteins into the mitochondrial inner membrane.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	19.4×	0.151
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC7A7	Transporter	yes		AA/rel_permease1, AminoAcid_Transporter
SPTA1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
ACIN1	Other/Unknown	no		SAP_dom, Nucleotide-bd_a/b_plait_sf, RSB_motif
OXA1L	Other/Unknown	no		YidC/ALB3/OXA1/COX18, YidC/Oxa/ALB_C

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
mononuclear cell	1
secondary oocyte	1
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
right lobe of thyroid gland	1
right uterine tube	1
sural nerve	1
body of pancreas	1
diaphragm	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC7A7	215	ubiquitous	marker	secondary oocyte, monocyte, mononuclear cell
SPTA1	147	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
ACIN1	294	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, sural nerve
OXA1L	290	ubiquitous	marker	hindlimb stylopod muscle, body of pancreas, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OXA1L	2,947
ACIN1	2,731
SLC7A7	1,584
SPTA1	1,551

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OXA1L	Q15070	17
SLC7A7	Q9UM01	5
SPTA1	P02549	3
ACIN1	Q9UKV3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective amino acid transport by SLC7A7 causes lysinuric protein intolerance (LPI)	1	1427.5×	0.024	SLC7A7
Apoptotic cleavage of cellular proteins	1	119.0×	0.062	ACIN1
Apoptotic execution phase	1	119.0×	0.062	ACIN1
Basigin interactions	1	109.8×	0.062	SLC7A7
Interaction between L1 and Ankyrins	1	92.1×	0.062	SPTA1
Amino acid transport across the plasma membrane	1	75.1×	0.062	SLC7A7
NCAM signaling for neurite out-growth	1	68.0×	0.062	SPTA1
Apoptosis	1	42.0×	0.062	ACIN1
Complex I biogenesis	1	41.4×	0.062	OXA1L
Programmed Cell Death	1	36.6×	0.062	ACIN1
ER to Golgi Anterograde Transport	1	33.2×	0.062	SPTA1
MAPK1/MAPK3 signaling	1	32.8×	0.062	SPTA1
Mitochondrial translation initiation	1	31.7×	0.062	OXA1L
Mitochondrial translation elongation	1	31.7×	0.062	OXA1L
Mitochondrial ribosome-associated quality control	1	30.7×	0.062	OXA1L
L1CAM interactions	1	30.1×	0.062	SPTA1
Mitochondrial translation termination	1	27.4×	0.062	OXA1L
COPI-mediated anterograde transport	1	27.4×	0.062	SPTA1
mRNA Splicing	1	27.4×	0.062	ACIN1
MAPK family signaling cascades	1	25.7×	0.062	SPTA1
Transport to the Golgi and subsequent modification	1	25.7×	0.062	SPTA1
Processing of Capped Intron-Containing Pre-mRNA	1	20.5×	0.074	ACIN1
RAF/MAP kinase cascade	1	15.3×	0.092	SPTA1
Asparagine N-linked glycosylation	1	15.0×	0.092	SPTA1
mRNA Splicing - Major Pathway	1	13.7×	0.097	ACIN1
Axon guidance	1	11.3×	0.112	SPTA1
Nervous system development	1	10.7×	0.112	SPTA1
Metabolism of RNA	1	10.4×	0.112	ACIN1
Membrane Trafficking	1	9.3×	0.121	SPTA1
Vesicle-mediated transport	1	8.7×	0.125	SPTA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
basic amino acid transmembrane transport	1	4213.0×	0.006	SLC7A7
obsolete regulation of arginine metabolic process	1	2106.5×	0.006	SLC7A7
porphyrin-containing compound biosynthetic process	1	1053.2×	0.006	SPTA1
mitochondrial protein quality control	1	1053.2×	0.006	OXA1L
protein insertion into mitochondrial inner membrane from matrix	1	842.6×	0.006	OXA1L
apoptotic chromosome condensation	1	702.2×	0.006	ACIN1
negative regulation of oxidoreductase activity	1	702.2×	0.006	OXA1L
mitochondrial proton-transporting ATP synthase complex assembly	1	526.6×	0.006	OXA1L
lymphocyte homeostasis	1	468.1×	0.006	SPTA1
negative regulation of ATP-dependent activity	1	421.3×	0.006	OXA1L
L-leucine transport	1	383.0×	0.006	SLC7A7
positive regulation of monocyte differentiation	1	383.0×	0.006	ACIN1
actin filament capping	1	383.0×	0.006	SPTA1
L-arginine transmembrane transport	1	351.1×	0.006	SLC7A7
plasma membrane organization	1	221.7×	0.009	SPTA1
negative regulation of mRNA splicing, via spliceosome	1	191.5×	0.010	ACIN1
amino acid transmembrane transport	1	183.2×	0.010	SLC7A7
protein tetramerization	1	156.0×	0.011	OXA1L
mitochondrial respiratory chain complex I assembly	1	102.8×	0.015	OXA1L
hemopoiesis	1	66.9×	0.021	SPTA1
erythrocyte differentiation	1	66.9×	0.021	ACIN1
positive regulation of T cell proliferation	1	64.8×	0.021	SPTA1
aerobic respiration	1	62.0×	0.021	OXA1L
mitochondrial translation	1	43.4×	0.029	OXA1L
regulation of cell shape	1	30.8×	0.038	SPTA1
actin filament organization	1	29.7×	0.038	SPTA1
RNA splicing	1	22.1×	0.050	ACIN1
actin cytoskeleton organization	1	19.8×	0.052	SPTA1
mRNA processing	1	19.7×	0.052	ACIN1
positive regulation of apoptotic process	1	14.2×	0.069	ACIN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACIN1	1	2
SLC7A7	0	0
SPTA1	0	0
OXA1L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACIN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACIN1	8	Binding:8
OXA1L	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACIN1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ACIN1
C	Druggable family + PDB, no drug	1	SLC7A7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SPTA1, OXA1L

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC7A7	0	—
SPTA1	0	—
OXA1L	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05706714	Not specified	COMPLETED	Th1, Th2, Th17 Phenotype in Urea Cycle Disorders