Gene Mapping In Chinese Pedigree With Hereditary Leukonychia Totalis And Identification Of Keratin 17 Gene Mutation

Leukonychia or white discoloration of the nails is a heterogeneous condition. It was classified morphologically into totalis, partialis, striata or punctuate. Leukonychia totalis is a rare nail disorder which may be hereditary or acquired. Hereditary or congenital leukonychia, is present since birth, with positive family history and has autosomal dominant inheritance. Acquired leukonychia totalis appears in early childhood. Up to date, only few studies about hereditary leukonychia totalis have been published, which most of those papers are case reports. Although some efforts have been put into clinical characterization, only histopathology and Human leukocyte antigen (HLA) classification of leukonychia totalis have been addressed. The genes responsible for leukonychia remain unkown, and there was no reported study on gene mapping and gene identification.This study performed a genome-wide scan in a Chinese Han pedigree with hereditary leukonychia totalis, localized the susceptibility region to chromosome 2 and sequenced susceptible gene keratin 17.Part â… : Genetic analysis of hereditary leukonychia totalisA Chinese family with leukonychia totalis hereditaris was recruited in this study. There are 34 persons in four generations and 16 (7 men, 9 women) of them were affected. All the data of clinical traits, general physical examination andlaboratory tests were collected for all alive family members. Blood samples from 28 members in four generation were collected. The genetic analysis shows it is autosomal dominant inheritance.Part II: Gene screening of hereditary leukonychia totalisWe conducted candidate clone strategy. Based on the functions of the gene and pathological feature of the similar diseases, keratin 17 was chosen as a candidate gene. The genomic sequence of keratin 17 was amplified by Polymerase Chain Reaction (PCR) in all the patients and the sibs, including 8 exons and the frank regions. The direct sequencing was conducted to perform the mutation screen. The result shows there are two single nucleotide polymorphisms (SNP) in the coding region of keratin 17 in this family and no mutation of keratin 17 was found. It suggests that keratin 17 may not the susceptible gene for hereditary leukonychia totalis.In conclusion, by genome screening using microsatellite markers and gene screening, we have successfully fine mapped the susceptible region of hereditary leukonychia totalis in Chinese and excluded keratin 17 as the susceptible gene. Further experiment need to be conducted to search out the possible susceptible gene for hereditary leukonychia totalis.Part III: Gene mapping of hereditary leukonychia totalisWe performed a whole genome scan in this Chinese family with leukonychia totalis hereditaris. 382 polymorphism markers on 22 autosomal chromosomes were used. The average genetic interval between markers was IOcM. Linkage analysis and haplotype analysis were used to localize the susceptible region to this disease. Parametric linkage analyses identified that the region (D2S117- D2S338) on chromosome 2q3 may harbor the susceptible genes. Fine mapping shows thatthree markers (D2S325, D2S2382 and D2S126) in this region achieved the maximum LOD score 3.19 (theta=0). The position in chromosome of this region was 2q32.3~2q37.2. The hereditary distance and physical distance was 45.22 cM and 40.5Mb respectively. It's the first time to locate the susceptible gene of hereditary leukonychia totalis on chromosome 2 in the world. It provides the strong molecular basis to make clear of the pathogenesis of hereditary leukonychia totalis.