Autosomal recessive cutis laxa type 2, classic type

Summary

Autosomal recessive cutis laxa type 2, classic type (MONDO:0009054) is a disease caused by ATP6V0A2 (GenCC Strong), with 3 cohort genes. The dominant Reactome pathway is Insulin receptor recycling (3 cohort genes).

At a glance

• Causal gene: ATP6V0A2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 57

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001476	Delayed closure of the anterior fontanelle	Obligate (100%)
HP:0000218	High palate	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000455	Broad nasal tip	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0000973	Cutis laxa	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0002187	Intellectual disability, profound	Very frequent (80-99%)
HP:0002208	Coarse hair	Very frequent (80-99%)
HP:0002361	Psychomotor deterioration	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0002761	Generalized joint laxity	Very frequent (80-99%)
HP:0003160	Abnormal isoelectric focusing of serum transferrin	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003199	Decreased muscle mass	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005272	Prominent nasolabial fold	Very frequent (80-99%)
HP:0005989	Redundant neck skin	Very frequent (80-99%)
HP:0006891	Thick cerebral cortex	Very frequent (80-99%)
HP:0007392	Excessive wrinkled skin	Very frequent (80-99%)
HP:0007457	Prominent veins on trunk	Very frequent (80-99%)
HP:0007552	Abnormal subcutaneous fat tissue distribution	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0009125	Lipodystrophy	Very frequent (80-99%)
HP:0011003	High myopia	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0025167	Fragmented elastic fibers in the dermis	Very frequent (80-99%)
HP:0100874	Thick hair	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001302	Pachygyria	Frequent (30-79%)
HP:0001305	Dandy-Walker malformation	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cutis laxa type 2, classic type
Mondo ID	MONDO:0009054
MeSH	C562632
Orphanet	357074
DOID	DOID:0070141
SNOMED CT	73856006
UMLS	C5679922
MedGen	1825992
GARD	0017546
Is cancer (heuristic)	no

Also known as: ARCL2, classic type · ARCL2, Debré type · ARCL2A · autosomal recessive cutis laxa type 2, Debre type · autosomal recessive cutis laxa type 2, Debré type

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited cutis laxa › autosomal recessive cutis laxa type 2, classic type

Related subtypes (13): craniofaciofrontodigital syndrome, arterial tortuosity syndrome, ALDH18A1-related de Barsy syndrome, geroderma osteodysplastica, occipital horn syndrome, RIN2 syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, PYCR1-related de Barsy syndrome, autosomal dominant cutis laxa, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, cutis laxa, autosomal recessive, type 2E, arterial tortuosity-bone fragility syndrome

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

1 retrieved; paginated sample, class counts are floors:

1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4540553	NM_012463.4(ATP6V0A2):c.235del (p.Leu79fs)	ATP6V0A2	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 5 · 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
ATP6V0A2	Strong	Autosomal recessive	autosomal recessive cutis laxa type 2, classic type	7
ATP6V1A	Strong	Autosomal recessive	autosomal recessive cutis laxa type 2D	11
ATP6V1E1	Strong	Autosomal recessive	autosomal recessive cutis laxa type 2C	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V0A2	Orphanet:2834	Wrinkly skin syndrome
ATP6V0A2	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type
ATP6V1A	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type
ATP6V1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP6V1E1	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V0A2	HGNC:18481	ENSG00000185344	Q9Y487	V-type proton ATPase 116 kDa subunit a 2	gencc,clinvar
ATP6V1A	HGNC:851	ENSG00000114573	P38606	V-type proton ATPase catalytic subunit A	gencc
ATP6V1E1	HGNC:857	ENSG00000131100	P36543	V-type proton ATPase subunit E 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V0A2	V-type proton ATPase 116 kDa subunit a 2	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
ATP6V1A	V-type proton ATPase catalytic subunit A	Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
ATP6V1E1	V-type proton ATPase subunit E 1	Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V0A2	Enzyme (other)	yes	7.1.2.1	V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
ATP6V1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_asu
ATP6V1E1	Other/Unknown	no		ATPase_V1_Esu, ATPase_E_C

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
middle temporal gyrus	2
skin of leg	1
stromal cell of endometrium	1
sural nerve	1
Brodmann (1909) area 23	1
endothelial cell	1
pons	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V0A2	239	ubiquitous	marker	skin of leg, sural nerve, stromal cell of endometrium
ATP6V1A	300	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, endothelial cell
ATP6V1E1	303	ubiquitous	marker	middle temporal gyrus, prefrontal cortex, pons

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1A	3,301
ATP6V1E1	2,187
ATP6V0A2	2,076

Intra-cohort edges

A	B	Sources
ATP6V0A2	ATP6V1A	string_interaction
ATP6V0A2	ATP6V1E1	intact, string_interaction
ATP6V1A	ATP6V1E1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V1A	P38606	8
ATP6V1E1	P36543	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V0A2	Q9Y487	81.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insulin receptor recycling	3	380.7×	5e-08	ATP6V0A2, ATP6V1A, ATP6V1E1
Transferrin endocytosis and recycling	3	368.4×	5e-08	ATP6V0A2, ATP6V1A, ATP6V1E1
ROS and RNS production in phagocytes	3	335.9×	5e-08	ATP6V0A2, ATP6V1A, ATP6V1E1
Ion channel transport	3	96.0×	2e-06	ATP6V0A2, ATP6V1A, ATP6V1E1
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	2	447.8×	8e-06	ATP6V1A, ATP6V1E1
Amino acids regulate mTORC1	2	133.6×	7e-05	ATP6V1A, ATP6V1E1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proton transmembrane transport	3	312.1×	2e-07	ATP6V0A2, ATP6V1A, ATP6V1E1
regulation of macroautophagy	3	295.6×	2e-07	ATP6V0A2, ATP6V1A, ATP6V1E1
cellular response to increased oxygen levels	2	1404.3×	2e-06	ATP6V0A2, ATP6V1A
Golgi lumen acidification	2	1123.5×	3e-06	ATP6V0A2, ATP6V1A
synaptic vesicle lumen acidification	2	624.1×	8e-06	ATP6V1A, ATP6V1E1
vacuolar acidification	2	488.5×	1e-05	ATP6V0A2, ATP6V1A
intracellular iron ion homeostasis	2	162.8×	8e-05	ATP6V0A2, ATP6V1A
endosomal lumen acidification	1	401.2×	0.003	ATP6V1A
intracellular pH reduction	1	401.2×	0.003	ATP6V1A
lysosomal lumen acidification	1	224.7×	0.005	ATP6V1A
ATP metabolic process	1	156.0×	0.007	ATP6V1A
immune response	1	15.7×	0.062	ATP6V0A2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V0A2	0	0
ATP6V1A	0	0
ATP6V1E1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATP6V1A	2	Binding:2
ATP6V1E1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP6V0A2	7.1.2.1	P-type H+-exporting transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ATP6V0A2
E	Difficult family or no structure, no drug	2	ATP6V1A, ATP6V1E1

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)
ATP6V0A2	0	—
ATP6V1A	2	—
ATP6V1E1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.