Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies.

Isolated autosomal recessive woolly hair/hypotrichosis (ARWH) is a rare hereditary hair disease characterized by tightly curled sparse hair at birth or in early infancy. Patients with ARWH consist of genetically heterogeneous groups. Woolly hair autosomal recessive 1 (ARWH1) (MIM #278150), woolly hair autosomal recessive 2 (ARWH2) (MIM #604379) and woolly hair autosomal recessive 3 (ARWH3) (MIM #616760) are caused by mutations in LPAR6, LIPH and KRT25, respectively. In addition, nonsense variants in C3ORF52 (*611956) were identified in ARWH patients. The frequencies of the mutations in the causative genes in ARWH patients are thought to differ by ethnicity and country/geographical area. Large numbers of ARWH families with LIPH mutations have been described only in populations from Japan, Pakistan and the Volga-Ural region of Russia. In that region of Russia, most ARWH families have an extremely prevalent founder mutation, the deletion of exon 4, in LIPH. In the Pakistani population, 47.2% of ARWH families had the disease due to LIPH mutations and 52.8% of them carried LPAR6 mutations. The prevalent, recurrent LIPH mutation c.659_660delTA (p.Ile220Argfs*29) was found in more than half of Pakistani ARWH families with LIPH mutations. Most Japanese ARWH families (98.7%) harbour LIPH mutations, including the two highly prevalent, recurrent LIPH mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn). In ARWH patients whose disease was due to LIPH, LPAR6 or C3ORF52 mutations, the loss of function of LIPH, LPAR6 or C3ORF52 leads to reduced LIPH-LPA-LPAR6 signalling, resulting in the decreased transactivation of EGFR signalling and the phenotype of underdeveloped hairs. Our recent prospective interventional study suggests that topical minoxidil might be a promising treatment for ARWH due to LIPH mutations, although sufficiently effective treatments have not been established for ARWH yet.