TY - JOUR
T1 - Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation
AU - Wang, Zhi Qiang
AU - Si, Lizhen
AU - Tang, Quan
AU - Lin, Debao
AU - Fu, Zhangjie
AU - Zhang, Jing
AU - Cui, Bin
AU - Zhu, Yufei
AU - Kong, Xianghua
AU - Deng, Min
AU - Xia, Yu
AU - Xu, Heng
AU - Le, Weidong
AU - Hu, Landian
AU - Kong, Xiangyin
N1 - Funding Information:
We thank all members of the TPT-PS family for participation in this study, and we thank Donghua Chen, Minhua Jin, and Jianqun Wang for their support. This work is supported by the National High Technology Research and Development Program of China (2006AA02Z330, 2006AA02A301), the National Basic Research Program of China (2007CB512202, 2007CB512100, 2004CB518603), the National Natural Science Foundation of China, Key Program (30530450), the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX1-YW-R-74), and the E-Institutes of Shanghai Municipal Education Commission.
PY - 2009/5/15
Y1 - 2009/5/15
N2 - Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. The genetic basis for FPH remains unknown. In this study, a six-generation Chinese family with FPH was subjected to a genome-wide scan for linkage analysis. Two-point linkage analysis mapped the locus for FPH at chromosome 12q21.31-q23.1, with a maximum two-point LOD score of 4.35 (Ø = 0.00) at D12S81. Haplotype analysis confined the locus within an interval of 9.09 cM, flanked by the markers D12S1667 and D12S2081. Mutation profiling of positional candidate genes detected a heterozygous transversion (c. 107A→G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution of a serine residue for an asparagine residue at codon 36 (p.N→S). This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family. Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLGN36S compared to wild-type control. To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLGN36S mutation, which has a gain-of-function effect on the melanin synthesis and opens a new avenue for exploration of the genetic mechanism of FPH.
AB - Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. The genetic basis for FPH remains unknown. In this study, a six-generation Chinese family with FPH was subjected to a genome-wide scan for linkage analysis. Two-point linkage analysis mapped the locus for FPH at chromosome 12q21.31-q23.1, with a maximum two-point LOD score of 4.35 (Ø = 0.00) at D12S81. Haplotype analysis confined the locus within an interval of 9.09 cM, flanked by the markers D12S1667 and D12S2081. Mutation profiling of positional candidate genes detected a heterozygous transversion (c. 107A→G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution of a serine residue for an asparagine residue at codon 36 (p.N→S). This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family. Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLGN36S compared to wild-type control. To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLGN36S mutation, which has a gain-of-function effect on the melanin synthesis and opens a new avenue for exploration of the genetic mechanism of FPH.
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U2 - 10.1016/j.ajhg.2009.03.019
DO - 10.1016/j.ajhg.2009.03.019
M3 - Article
C2 - 19375057
AN - SCOPUS:65149096689
VL - 84
SP - 672
EP - 677
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -