HR – Marie Unna hereditary hypotrichosis

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant form of non‐syndromic hereditary hypotrichosis characterized by sparse, wiry scalp hair, eyebrows, and eyelashes (HP:0001599). Loss‐of‐function mutations in an inhibitory upstream open reading frame (U2HR) of the HR gene (HGNC:5172) have been robustly linked to MUHH across multiple ancestries.

Initial linkage and sequencing in a large Chinese pedigree identified a pathogenic initiation codon mutation c.1A>G (p.Met1Val) segregating with disease in 13 affected relatives over five generations (PMID:19122663). Subsequent screening of 18 additional independent families from diverse populations uncovered a spectrum of U2HR defects, including loss of initiation, delayed termination, nonsense, and missense mutations, in a total of 19 families (PMID:19122663). A sporadic Chinese patient harbored the novel variant c.14C>T (p.Pro5Leu), further extending the mutation spectrum (PMID:22155146).

All reported MUHH‐associated variants in U2HR act via loss of inhibition of the downstream HR physiological ORF. Recurrent mutations include c.1A>G (p.Met1Val) and c.14C>T (p.Pro5Leu), with no evidence of founder effects. Carrier frequency and population prevalence remain to be defined.

Functional assays demonstrate that U2HR mutations universally increase translation of the main HR ORF, supporting a gain‐of‐function dosage mechanism. In vitro reporter assays and transfection studies confirm elevated HR protein levels in cells harboring mutant U2HR alleles (PMID:19122663). The Hr(Hp) mouse model carrying a gain‐of‐function T403A mutation phenocopies MUHH, showing hair follicle dysregulation and transcriptomic changes in key hair‐cycle genes (PMID:21083932).

No studies dispute the causal link between HR U2HR mutations and MUHH. Taken together, the breadth of genetic evidence across 19 families, consistent segregation, and concordant functional data establish a definitive gene–disease relationship.

Key take‐home: HR U2HR loss‐of‐function mutations cause autosomal dominant Marie Unna hereditary hypotrichosis, providing a clear target for genetic diagnosis, counseling, and future therapeutic exploration.

References

• Nature Genetics • 2009 • Loss‐of‐function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. PMID:19122663
• European Journal of Dermatology • 2012 • Identification of a novel U2HR mutation c.14C>T in a Chinese patient with Marie Unna hereditary hypotrichosis. PMID:22155146
• The Journal of Dermatology • 2019 • Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family. PMID:30809827
• BMC Genomics • 2010 • Gene expression profile of the skin in the 'hairpoor' (HrHp) mice by microarray analysis. PMID:21083932

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