An Autosomal Recessive Form of Monilethrix Is Caused by Mutations in DSG4: Clinical Overlap with Localized Autosomal Recessive Hypotrichosis

Abstract

Monilethrix is a structural defect of the hair shaft usually inherited in an autosomal dominant fashion and caused by mutations in the hHb1, hHb3, and hHb6 keratin genes. Autosomal recessive inheritance in this disease has been sporadically reported. We encountered 12 Jewish families from Iraq, Iran, and Morocco with microscopic findings of monilethrix, but with no evidence of vertical transmission. Since no mutations were found in these three hair keratin genes, we examined nine chromosomal regions containing gene clusters encoding skin and hair genes. On chromosome 18q, a common haplotype in the homozygous state was found among all seven Iraqi patients, but not in 20 controls (P<0.0001). Sequencing of the main candidate gene from this region revealed four different mutations in desmoglein 4 (DSG4). Mutations in DSG4 have been previously reported in localized autosomal recessive hypotrichosis, a disorder that shares the clinical features of monilethrix but lacks the characteristic microscopic appearance of the hair shaft. Our findings have important implications for genetic counseling to monilethrix patients and families, and suggest that DSG4-associated hair disorders may be more common than previously thought.

Current Genetics in Hair Diseases

“…The eyebrows and beard are less dense than normal, and the axillary hair, pubic hair, and eyelashes look normal in most cases. It is noteworthy that hair shafts of affected individuals with DSG4 mutations are fragile and often show moniliform hair [33][34][35]. Therefore, the DSG4 can also be regarded as a causative gene for autosomal recessive monilethrix.…”

Diseases of epidermal keratins and their linker proteins

“…This amino acid substitution is located within a highly conserved motif (RAL) corresponding to the HAV region of classical cadherins, a domain that is important in cell-cell adhesion. In 2006, further missense, splice site, frameshift and nonsense mutations in the DSG4 gene were reported [85][86][87]. However, the phenotype in these cases was described as autosomal recessive monilethrix.…”

Cadherins as Targets for Genetic Diseases

“…Monilethrix is inherited either as a dominant or a recessive disorder. Homozygous mutations in DSG4 were identified in monilethrix-affected patients (Schaffer et al 2006;Shimomura et al 2006;Zlotogorski et al 2006). The existence of potential modifying genes or different types/combinations of mutations may explain the interfamilial variations in phenotype among individuals carrying DSG4 mutations.…”