HR

protein-coding

HR lysine demethylase and nuclear receptor corepressor

Gene summary

This gene encodes a protein that is involved in hair growth. This protein functions as a transcriptional corepressor of multiple nuclear receptors, including thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptors, and it interacts with histone deacetylases. The translation of this protein is modulated by a regulatory open reading frame (ORF) that exists upstream of the primary ORF. Mutations in this upstream ORF cause Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant form of genetic hair loss. Mutations in this gene also cause autosomal recessive congenital alopecia and atrichia with papular lesions, other diseases resulting in hair loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

Previous symbols:

ALUNC

MANE transcript

NM_005144.5

Inheritance

AR, AD

ClinVar variants

P:26U:287B:106

Top phenotype

Atrichia with papular lesions; Alopecia universalis congenita

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr8:22,114,419-22,133,384

External References & Databases

Ensembl (ENSG00000168453)

Transcript & Mutation Effects

hg38 • Region Span ~19.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

atrichia with papular lesionsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008847

Submitter: Labcorp Genetics (formerly Invitae)

atrichia with papular lesionsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008847

Submitter: Ambry Genetics

alopecia universalis congenitaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008757

Submitter: G2P

Marie Unna hereditary hypotrichosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018631

Submitter: Orphanet

alopecia universalis congenitaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008757

Submitter: Orphanet

atrichia with papular lesionsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008847

Submitter: Orphanet

atrichia with papular lesionsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008847

Submitter: PanelApp Australia

hypotrichosis 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100522

Submitter: Labcorp Genetics (formerly Invitae)

atrichia with papular lesionsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008847

Submitter: G2P

alopecia universalis congenitaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008757

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Atrichia with papular lesions; Alopecia universalis congenitaAR

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 13150805; 13763141; 5570254; 9758627; 10205263; 10827399; 11410842; 12271294; 11982770; 12880440; 17869066; 10417283; 11069461; 10854110; 10777357; 15149494; 17680008; 21272494; 21919222; 22584530

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HR variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 218

not providedTotal: 208

Alopecia universalis congenitaTotal: 118

Atrichia with papular lesionsTotal: 116

HR-related disorderTotal: 24

not specifiedTotal: 22

Intellectual disability, autosomal dominant 14Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005144.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	54 clinvar	12 clinvar	77
missense	2 clinvar	1 clinvar	272 clinvar	28 clinvar	12 clinvar	315
nonsense	6 clinvar	3 clinvar	1 clinvar			10
start loss						0
frameshift	6 clinvar	5 clinvar				11
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	3 clinvar			6
Total	16	10	287	82	24	419

Highest pathogenic variant AF is 0.000021139056

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005144.5	RefSeq	NP_005135.2	18	MANE Select
ENST00000381418.9	Ensembl	ENSP00000370826.4	18	MANE Select
NM_018411.4	RefSeq	NP_060881.2	17	Standard
ENST00000312841.10	Ensembl	ENSP00000326765.8	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
histone H3-K9 demethylation
negative regulation of transcription, DNA-templated
oxidation-reduction process

Molecular Function

transcription regulatory region sequence-specific DNA binding
DNA binding
DNA-binding transcription factor activity
transcription corepressor activity
oxidoreductase activity

Cellular Component

chromatin
nucleus
nucleoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381418
Coding exons: 18
Length: 18970
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.674	652	702	0.928	0.0000448	7481
Missense (PolyPhen)		164	204.32	0.80266		2364
Synonymous	-0.409	314	305	1.03	0.0000201	2538
Loss of Function	3.80	25	55.6	0.450	0.00000301	556

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00023	0.00022	rare
South Asian	0.00014	0.00013	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that specifically demethylates both mono- and dimethylated 'Lys-9' of histone H3. May act as a transcription regulator controlling hair biology (via targeting of collagens), neural activity, and cell cycle. {ECO:0000269|PubMed:24334705}.;
Disease: DISEASE: Alopecia universalis congenita (ALUNC) [MIM:203655]: A rare disorder characterized by loss of hair from the entire body. No hair are present in hair follicles on skin biopsy. {ECO:0000269|PubMed:12406339, ECO:0000269|PubMed:24334705, ECO:0000269|PubMed:9445480, ECO:0000269|PubMed:9736769}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrichia with papular lesions (APL) [MIM:209500]: An autosomal recessive disease characterized by papillary lesions over most of the body and almost complete absence of hair. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypotrichosis 4 (HYPT4) [MIM:146550]: An autosomal dominant condition characterized by reduced amount of hair, alopecia, little or no eyebrows, eyelashes or body hair, and coarse, wiry, twisted hair in early childhood. {ECO:0000269|PubMed:19122663, ECO:0000269|PubMed:24961381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.695
RVIS EVS: 1.24
RVIS percentile EVS: 93.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.708

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium