A large duplication in LIPH underlies autosomal recessive hypotrichosis simplex in four Middle Eastern families.

Autosomal recessive hypotrichosis simplex (ARHS) manifests with paucity of hair appearing during early childhood. We assessed four affected families. We initially genotyped three of these families for a panel of microsatellite markers spanning all ARHS-associated loci and obtained data suggesting linkage to 3q27, encompassing LIPH, which had previously been shown to be associated with ARHS. Accordingly, a homozygous duplication mutation in exon 2 of this gene (c.280_369dup; p.Gly94_Lys123dup) was found to segregate with the disease in all the families. Through the identification of the first duplication mutation in the human LIPH gene, we provide further evidence supporting a role for the phospholipase signalling pathway in hair growth and differentiation.

Loss-of-function mutations in the filaggrin gene and alopecia areata: strong risk factor for a severe course of disease in patients comorbid for atopic disease.

Alopecia areata (AA) is a common dermatological disease, which affects nearly 2% of the general population. Association of AA with atopic disease has been repeatedly reported. Loss-of-function mutations in the filaggrin gene (FLG) may be considered as promising candidates in AA, as they have been observed to be a strong risk factor in atopic dermatitis. The FLG mutations R501X and 2282del4 were genotyped in a large sample of AA patients (n=449) and controls (n=473). Although no significant association was observed in the patient sample overall, FLG mutations were significantly associated with the presence of atopic dermatitis among AA patients. Furthermore, the presence of FLG mutations had a strong impact on the clinical course of AA in comorbid patients. For example, 19 of the 22 mutation carriers among AA patients with atopic dermatitis showed a severe form of the disease (P=0.003; odds ratio (OR)=5.47 (95% confidence interval (CI): 1.59-18.76)). In conclusion, our data suggest that when AA occurs in conjunction with FLG-associated atopic disorder, the clinical presentation of AA may be more severe.

Identification of mutations in the human hairless gene in two new families with congenital atrichia.

Congenital atrichia (AUC) is a form of isolated alopecia with an autosomal recessive mode of inheritance. Patients are born with normal hair but this is shed almost completely during the first weeks or months of life and never regrows. In many families the development of papular lesions is noted as an additional phenotypic feature, which defines a related phenotype designated as atrichia with papular lesions (APL). Using positional cloning strategies and the molecular findings in hairless recessive (hr/hr) mice, an animal model for AUC, mutations in the human hairless gene (HR) have been identified as a cause of AUC and APL. To date, more than 20 different mutations of the HR gene have been reported in AUC and APL including different mutation types scattered over the entire HR gene length. In this report, we describe two families of Saudi Arabian and Jewish Iranian origin comprising a number of individuals with clinical features suggestive of AUC. We therefore hypothesized that affected members may carry mutations in the HR gene. After sequencing the complete coding region of the HR gene in the Saudi Arabian family, we identified a homozygous insertion of a G (c.2661dupG; p.Thr888DfsX38) in exon 12, resulting in a premature stop codon. In a Jewish Iranian patient, we identified a homozygous splice site mutation c.1557-1G > T in intron 4. The latter mutation has been previously reported in a compound heterozygous state. In the present report, we describe the second exonic insertion mutation in the human HR gene and the first mutation in exon 12. Our study emphasizes the importance of sequencing the complete coding sequence and exon/intron junctions in the molecular diagnostics of AUC and APL.