Localization of the Netherton syndrome gene to chromosome 5q32, by linkageanalysis and homozygosity mapping

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessi ve disorder characterized by congenital ichthyosis, a specific hair-shaft d efect (trichorrhexis invaginata), and atopic manifestations. Infants with t his syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chrom osome 5q32, by linkage analysis and homozygosity mapping in 20 families aff ected with NS. Significant evidence for linkage (maximum multipoint LOD sco re 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS l ocus between markers D5S463 and D5S2013, within an <3.5-cM. genetic interva l. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase 1 alpha, the alpha subunit of retinal r od cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adren ergic receptor beta 2, and the diastrophic dysplasia sulfate-transporter ge ne, as well as the 38 expressed-sequence tags mapped within the critical re gion, are not obvious candidates. Our study is the first step toward the po sitional cloning of the NS gene. This finding promises a better understandi ng of the molecular mechanisms that control epidermal differentiation and i mmunity.