Localization of the Netherton Syndrome Gene to Chromosome 5q32, by Linkage Analysis and Homozygosity Mapping

Abstract

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an !3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ia, the a subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor b2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.

Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2‐like tumor‐associated macrophages expressing the novel CD20 homolog MS4A8A

“…23 Mutations and polymorphisms of the protease inhibitor SPINK5 are associated with Netherton syndrome and atopy characterized by a dysregulated Th2 response and elevated IgE levels indicating a T-cell regulatory function. 24,33 SORL1 is a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP). 34 Blocking APP in metastatic malignant melanoma impairs the proliferation of melanoma cells and leads to their terminal differentiation.…”

Prenatal diagnosis of Comel-Netherton syndrome with PGD, case report and review article

“…There are some articles about prenatal diagnosis of C-NS with amniocentesis or chorionic villus sampling in literature [21,32,33]. This study is first report of ICSI pregnancy with PGD in C-NS.…”

“…The recent identification of the defective gene in C-NS made DNA-based prenatal diagnosis possible [21]. SPINK5 (serin protease inhibitor Kazal-type 5) encodes the Kazal-type serin protease inhibitor domains.…”

Immunoglobulin E in primary immunodeficiency diseases

“…Using these sibships in a genome-wide linkage-screen, NS was mapped to a 4 cM interval on chromosome 5q32 (135). Evaluation of candidate genes within this region revealed that NS is caused by mutations in the serine protease inhibitor gene SPINK5 (136).…”