A novel locus for autosomal recessive form of hypotrichosis maps to chromosome 3q26.33-q27.3.

G enetic conditions affecting hair structure or the hair growth cycle may be isolated or they may occur as part of complex syndromes with associated abnormalities of other ectodermal appendages. Defective hair structure caused by mutations in key hair structural proteins can result in severe alopecia. The best characterised conditions at the molecular level in this category are monilethrix (MIM 158000) and Netherton syndrome 3 (MIM 256500). Monilethrix is an autosomal dominant disorder in which alopecia is the presenting manifestation; however, the degree of alopecia is variable between patients and during different time periods for the same individual. Causative mutations have been identified in the keratin hair basic 6 gene (HB6, MIM 601928) and the keratin hair basic 1 gene (HB1, MIM 602153). Netherton syndrome is a rare autosomal recessive condition characterised by ‘‘bamboo hair’’ (trichorrhexis invaginata), congenital ichthyosiform erythroderma, and atopic diathesis. Serine protease inhibitor, Kazal-type 5 gene (SPINK5, MIM 605010), located on chromosome 5q31–q32, encodes a 15 domain serine protease inhibitor and is mutated in Netherton syndrome. Structural hair shaft defects are also a feature of Menkes kinky hair syndrome (MIM 309400). Menkes disease, with X linked inheritance, is caused by mutations in the gene encoding Cu transporting ATPase, ATP7A (MIM 300011). Isolated forms of alopecia include congenital atrichia and different forms of hypotrichosis, which may represent a dysregulation of the hair growth cycle and remodelling. Autosomal recessive congenital atrichia (MIM 203655) is the most extreme example of hair loss. In affected individuals with this form of alopecia, hair is typically absent from the scalp with shedding shortly after birth. Congenital atrichia has been linked to 8p21, where several mutations of the hairless gene (HR, MIM 602302) have been reported as the underlying cause of congenital atrichia. 9 Marie Unna hereditary hypotrichosis (MUHH, MIM 146550) is an autosomal dominant disorder characterised by abnormal hair structure at birth, or soon after birth, with progressive hair loss leading to varying degrees of alopecia in adults. MUHH has been mapped to chromosome 8p21 in the vicinity of the hairless gene. Hypotrichosis simplex (HTS, MIM 605389) is an autosomal dominant disorder that can affect all bodily hair or can be limited to the scalp. Levy-Nissenbaum et al found nonsense mutations in corneodesmosin gene (CDSN, MIM 602593), located on chromosome 6p21.3, in three families with hypotrichosis simplex of the scalp (HTSS, MIM 146520). In autosomal recessive localised hereditary hypotrichosis (LAH, MIM 607903), the affected individuals show hypotrichosis restricted to the scalp, chest, arms, and legs. Facial hair, including the eyebrows and beard, is less dense, and axillary, pubic hair and eyelashes are unaffected. LAH has been linked to chromosomal location 18q21.1 13 which contains a cluster of desmoglein and desmocollin genes. Recently, mutations in the desmoglein 4 gene (DSG4, MIM 607892) have been implicated in LAH. We studied a highly consanguineous family with the autosomal recessive form of hereditary hypotrichosis. After exclusion of all the known loci, a genome scan was undertaken which led to the identification of a novel locus, AH, for this form of hereditary hypotrichosis, mapped to chromosome 3q26.33–q27.3 and flanked by markers D3S2314 and D3S1602.