Hypotrichosis 8

Summary

Hypotrichosis 8 (MONDO:0010206) is a disease caused by LPAR6 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: LPAR6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotrichosis 8
Mondo ID	MONDO:0010206
MeSH	C566950
OMIM	278150
DOID	DOID:0110705
UMLS	C3279470
MedGen	481100
GARD	0015247
Is cancer (heuristic)	no

Also known as: hypotrichosis 8 · hypotrichosis caused by mutation in LPAR6 · hypotrichosis type 8 · hypotrichosis, localized, autosomal recessive 3 · HYPT8 · LAH3 · LPAR6 hypotrichosis · woolly hair, autosomal recessive 1, with or without hypotrichosis

Data availability: 21 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hypotrichosis › hypotrichosis 8

Related subtypes (18): hypotrichosis of eyelid, hypotrichosis 2, congenital hypotrichosis with juvenile macular dystrophy, hypotrichosis 7, hypotrichosis 1, hypotrichosis 6, hypotrichosis 3, hypotrichosis 9, hypotrichosis 10, hypotrichosis 11, hypotrichosis 12, hypotrichosis 13, Marie Unna hereditary hypotrichosis, Basaran Yilmaz syndrome, congenital hypotrichosis milia, hypotrichosis 14, hypotrichosis 15, hypotrichosis 16

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

21 retrieved; paginated sample, class counts are floors:

11 likely pathogenic, 5 pathogenic, 2 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
217303	NM_181534.4(KRT25):c.950T>C (p.Leu317Pro)	KRT25	Pathogenic	criteria provided, single submitter
1323245	NM_000321.3(RB1):c.1695+30914_1695+30917dup	LPAR6	Pathogenic	criteria provided, multiple submitters, no conflicts
1685927	NM_001162498.3(LPAR6):c.1A>G (p.Met1Val)	LPAR6	Pathogenic	criteria provided, single submitter
1802233	NM_001162498.3(LPAR6):c.207_210dup (p.Pro71fs)	LPAR6	Pathogenic	criteria provided, single submitter
1829	NM_001162498.3(LPAR6):c.565G>A (p.Glu189Lys)	LPAR6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506997	NM_001162498.3(LPAR6):c.145C>T (p.Arg49Ter)	LPAR6	Pathogenic	criteria provided, single submitter
1827	NM_001162498.3(LPAR6):c.562A>T (p.Ile188Phe)	RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1824	NM_001162498.3(LPAR6):c.463C>T (p.Gln155Ter)	LPAR6	Likely pathogenic	criteria provided, single submitter
1828	NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)	LPAR6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
217499	NM_001162498.3(LPAR6):c.188A>T (p.Asp63Val)	LPAR6	Likely pathogenic	criteria provided, single submitter
2505340	NM_001162498.3(LPAR6):c.742A>T (p.Asn248Tyr)	LPAR6	Likely pathogenic	criteria provided, single submitter
2505341	NM_001162498.3(LPAR6):c.830T>C (p.Leu277Pro)	LPAR6	Likely pathogenic	criteria provided, single submitter
2505342	NM_001162498.3(LPAR6):c.833G>A (p.Cys278Tyr)	LPAR6	Likely pathogenic	criteria provided, single submitter
3250465	NM_001162498.3(LPAR6):c.924del (p.Val309fs)	LPAR6	Likely pathogenic	criteria provided, single submitter
3367022	NM_001162498.3(LPAR6):c.255del (p.Asp86fs)	LPAR6	Likely pathogenic	criteria provided, single submitter
3768194	NM_001162498.3(LPAR6):c.736A>G (p.Asn246Asp)	LPAR6	Likely pathogenic	criteria provided, single submitter
3891587	NM_001162498.3(LPAR6):c.787_788del (p.Cys263fs)	LPAR6	Likely pathogenic	criteria provided, single submitter
592094	NM_001162498.3(LPAR6):c.373_374del (p.Lys125fs)	LPAR6	Likely pathogenic	criteria provided, single submitter
30780	NM_001162498.3(LPAR6):c.587C>T (p.Pro196Leu)	LPAR6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699007	NM_001162498.3(LPAR6):c.107G>A (p.Cys36Tyr)	LPAR6	Uncertain significance	criteria provided, single submitter
2505339	NM_001162498.3(LPAR6):c.8G>C (p.Ser3Thr)	LPAR6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · 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
LPAR6	Strong	Autosomal recessive	hypotrichosis 8	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LPAR6	Orphanet:170	Woolly hair
LPAR6	Orphanet:55654	Hypotrichosis simplex
KRT25	Orphanet:170	Woolly hair
RB1	Orphanet:1587	Monosomy 13q14 syndrome
RB1	Orphanet:357027	Hereditary retinoblastoma
RB1	Orphanet:357034	Non-hereditary retinoblastoma
RB1	Orphanet:668	Osteosarcoma
RB1	Orphanet:70573	Small cell lung cancer

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
LPAR6	HGNC:15520	ENSG00000139679	P43657	Lysophosphatidic acid receptor 6	gencc,clinvar
KRT25	HGNC:30839	ENSG00000204897	Q7Z3Z0	Keratin, type I cytoskeletal 25	clinvar
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LPAR6	Lysophosphatidic acid receptor 6	Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA).
KRT25	Keratin, type I cytoskeletal 25	Essential for the proper assembly of type I and type II keratin protein complexes and formation of keratin intermediate filaments in the inner root sheath (irs).
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.

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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LPAR6	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
KRT25	Other/Unknown	no		Keratin_I, IF_rod_dom
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom

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
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
skin of hip	1
upper arm skin	1
choroid plexus epithelium	1
epithelium of nasopharynx	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LPAR6	269	ubiquitous	marker	gingival epithelium, gingiva, lower esophagus mucosa
KRT25	70	tissue_specific	marker	upper arm skin, skin of hip, male germ line stem cell (sensu Vertebrata) in testis
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RB1	4,374
KRT25	986
LPAR6	822

Intra-cohort edges

A	B	Sources
KRT25	LPAR6	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RB1	P06400	19
LPAR6	P43657	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT25	Q7Z3Z0	75.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Defective translocation of RB1 mutants to the nucleus	1	3806.7×	0.008	RB1
Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes	1	951.7×	0.008	RB1
Replication of the SARS-CoV-1 genome	1	951.7×	0.008	RB1
Replication of the SARS-CoV-2 genome	1	951.7×	0.008	RB1
Nucleotide-like (purinergic) receptors	1	634.4×	0.009	LPAR6
P2Y receptors	1	317.2×	0.013	LPAR6
Positive Regulation of CDH1 Gene Transcription	1	317.2×	0.013	RB1
Inhibition of replication initiation of damaged DNA by RB1/E2F1	1	271.9×	0.013	RB1
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	223.9×	0.014	RB1
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	211.5×	0.014	RB1
Aberrant regulation of mitotic exit in cancer due to RB1 defects	1	173.0×	0.015	RB1
RUNX2 regulates osteoblast differentiation	1	152.3×	0.016	RB1
Oncogene Induced Senescence	1	112.0×	0.019	RB1
Nuclear events stimulated by ALK signaling in cancer	1	108.8×	0.019	RB1
Cyclin E associated events during G1/S transition	1	95.2×	0.020	RB1
Cyclin A:Cdk2-associated events at S phase entry	1	88.5×	0.020	RB1
Cyclin D associated events in G1	1	77.7×	0.022	RB1
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	1	56.8×	0.028	RB1
Condensation of Prophase Chromosomes	1	52.1×	0.029	RB1
Formation of the cornified envelope	1	29.3×	0.049	KRT25
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.049	RB1
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.053	LPAR6
GPCR ligand binding	1	21.4×	0.058	LPAR6
G alpha (q) signalling events	1	19.1×	0.061	LPAR6
Keratinization	1	18.6×	0.061	KRT25
GPCR downstream signalling	1	14.5×	0.075	LPAR6
Signaling by GPCR	1	13.4×	0.078	LPAR6
Developmental Biology	1	4.8×	0.200	KRT25
Signal Transduction	1	3.4×	0.267	LPAR6

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
sister chromatid biorientation	1	1872.4×	0.007	RB1
glial cell apoptotic process	1	1872.4×	0.007	RB1
maintenance of mitotic sister chromatid cohesion	1	1404.3×	0.007	RB1
regulation of lipid kinase activity	1	1404.3×	0.007	RB1
positive regulation of extracellular matrix organization	1	1404.3×	0.007	RB1
positive regulation of collagen fibril organization	1	1404.3×	0.007	RB1
negative regulation of myofibroblast differentiation	1	1404.3×	0.007	RB1
negative regulation of hepatocyte apoptotic process	1	936.2×	0.008	RB1
enucleate erythrocyte differentiation	1	702.2×	0.008	RB1
protein localization to chromosome, centromeric region	1	702.2×	0.008	RB1
positive regulation of transcription regulatory region DNA binding	1	702.2×	0.008	RB1
negative regulation of glial cell proliferation	1	561.7×	0.009	RB1
cell morphogenesis involved in neuron differentiation	1	510.7×	0.010	RB1
positive regulation of macrophage differentiation	1	401.2×	0.011	RB1
positive regulation of mitotic metaphase/anaphase transition	1	401.2×	0.011	RB1
hepatocyte apoptotic process	1	351.1×	0.011	RB1
striated muscle cell differentiation	1	330.4×	0.011	RB1
hair cycle	1	312.1×	0.011	KRT25
glial cell proliferation	1	295.6×	0.011	RB1
negative regulation of protein kinase activity	1	280.9×	0.011	RB1
myoblast differentiation	1	280.9×	0.011	RB1
neuron maturation	1	267.5×	0.011	RB1
chromosome organization	1	193.7×	0.013	RB1
tissue homeostasis	1	187.2×	0.013	RB1
negative regulation of apoptotic signaling pathway	1	187.2×	0.013	RB1
blastocyst hatching	1	181.2×	0.013	LPAR6
digestive tract development	1	175.5×	0.013	RB1
hair follicle morphogenesis	1	165.2×	0.014	KRT25
negative regulation of smoothened signaling pathway	1	151.8×	0.015	RB1
aortic valve morphogenesis	1	144.0×	0.015	RB1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

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
RB1	1	2
LPAR6	0	0
KRT25	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBVACICLIB	2	RB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RB1	59	Binding:59
LPAR6	5	Binding:4, Functional:1

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

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)
EBVACICLIB	2	RB1

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	RB1
C	Druggable family + PDB, no drug	1	LPAR6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KRT25

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LPAR6	5	—
KRT25	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.