Molecular Genetic Analyses Of A Chinese Families With Hypohidrotic Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia (HED) is a syndrome which found to occur worldwide, with an estimated incidence of 1 per 100,000 births. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin. HED is primarily characterized by the partial or complete absence of certain sweat glands (eccrine glands), causing the lack of or diminished sweating (anhidrosis or hypohidrosis), heat intolerance, and fever, abnormally sparse hair (hypotrichosis), and the absence (anodontia or hypodontia) and/or malformation of certain teeth. It can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns. However, X-linked HED (XLHED) is the most common form of HED. If unrecognized, XLHED is one of the causes of fever of unknown origin, repeated bronchitis, and sudden death during infancy and early childhood. Mutations in eight genes were identified to cause hypohidrotic ectodermal dysplasia, including six genes which are responsible for autosomal hypohidrotic ectodermal dysplasia, two genes for XLHED. Mutations in the EDA gene, which encodes ectodysplasin-A, are responsible for X-linked HED(XLHED); Whereas mutations in the IKBKG gene, which encodes NF-kappa-B essential modulator(NEMO), may cause both hypohidrotic ectodermal dysplasia and immunodeficiency(HED/ID).In the present study, we clinically identified a Chinese Han family with XLHED but no immunodeficiency. Linkage analysis of the Chinese XLHED family with two known genes(EDA, IKBKG) on chromosome X suggested that the EDA gene was responsible for the disease phenotype. Then direct DNA sequence analysis of the entire coding region and exon–intron boundaries of EDA identified a novel mutation, c.573₅74insT, in two affected males and one carrier female. Restriction fragment length polymorphism (RFLP) analysis showed that the mutation was not present in 200 controls. The 1-bp insertion mutation resulted in a frameshift, which causes premature termination of EDA polypeptide and truncation of the EDA protein. These results suggest that the c.573₅74insT mutation of the EDA gene is a cause for XLHED in the family. Paternal testing with multiple informative microsatellite markers from various chromosomes confirmed the familial relationship of individual II-4 with both parents. These results demonstrate that the c.573-574insT insertion is a de novo mutation. To the best of our knowledge, this is the first de novo insertion mutation of EDA described...