HR – Atrichia with Papular Lesions

Hairless (HR) is a zinc‐finger transcriptional corepressor implicated in the regulation of hair follicle cycling. Pathogenic biallelic variants in HR underlie atrichia with papular lesions (APL; MONDO:0008847), a rare autosomal recessive form of irreversible alopecia characterized by early complete hair loss and development of keratin‐filled papules.

Genetic analyses across multiple consanguineous and nonconsanguineous families have identified over 25 unrelated APL probands harboring homozygous or compound heterozygous loss‐of‐function and missense variants in HR (PMID:15953070; PMID:16211417; PMID:26680117). Variant classes include splice site mutations (e.g., c.2847-1G>A), frameshifts (e.g., c.3435del (p.Ser1146LeufsTer?)), nonsense alleles (e.g., c.3515G>A (p.Gln585Ter)), and recurrent founder deletions (c.3435delC) (PMID:15953070; PMID:12271294).

Segregation of HR variants with APL has been demonstrated in at least 10 families, including compound heterozygous siblings and multiple consanguineous pedigrees, totaling 19 additional affected relatives (PMID:12271294; PMID:16211417). Genotype–phenotype correlations are consistent with complete loss of HR function leading to follicular cyst formation and absence of mature follicles.

Functional assays reveal that most pathogenic HR missense mutations abolish VDR corepressor activity, impair HDAC1 recruitment, and disrupt histone H3K9 demethylase function (PMID:17609203; PMID:24334705). Rescue of HR demethylase activity in vitro confirms the mechanistic basis of pathogenicity and concordance with the human APL phenotype.

No robust conflicting evidence has been reported; one variant (E583V) retains normal corepressor activity and may represent a benign polymorphism (PMID:17609203). Overall, the genetic, segregation, and functional data meet ClinGen criteria for a Strong gene–disease association.

Key take‐home: Biallelic HR loss‐of‐function variants reliably diagnose APL and inform genetic counselling, guiding avoidance of ineffective alopecia treatments and enabling carrier screening.

References

• Clinical and Experimental Dermatology • 2005 • Identification of a recurrent mutation in the human hairless gene underlying atrichia with papular lesions. PMID:15953070
• Archives of Dermatological Research • 2005 • Atrichia with papular lesions in two Pakistani consanguineous families resulting from mutations in the human hairless gene. PMID:16211417
• International Journal of Dermatology • 2016 • Disease causing homozygous variants in the human hairless gene. PMID:26680117
• The Journal of Biological Chemistry • 2007 • Interactions of the vitamin D receptor with the corepressor hairless: analysis of hairless mutants in atrichia with papular lesions. PMID:17609203
• FASEB Journal • 2014 • Hairless is a histone H3K9 demethylase. PMID:24334705
• Journal of the American Academy of Dermatology • 2002 • Atrichia with papular lesions resulting from compound heterozygous mutations in the hairless gene: A lesson for differential diagnosis of alopecia universalis. PMID:12271294

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