Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC)
Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC)
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DOI：
10.1136/jmg.2008.061234
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Ahmad, W.
中科院分区：
文献类型：
--
作者：
Tariq, M.;Azeem, Z.;Ahmad, W.
背景资料：孤立性先天性杵指（ICNC）是一种罕见的常染色体隐性遗传病，其特征是由于结缔组织增生和甲基质功能异常而导致手指和脚趾末端变大，指甲变厚。在本研究中，我们调查了一个大的巴基斯坦家庭与11个受影响的个人遗传性先天性甲杵作为一个单一的不变的临床特征，没有任何相关的外胚层，骨骼或全身imperfect.Objective：要确定一个基因的ICNC phenotype.Methods：全基因组纯合性连锁作图策略，以确定基因引起ICNC。结果：ICNC的致病基因位于染色体4q32.3-q34.1的13.25cM区域，该区域为ICNC的致病位点。根据基于序列的物理图谱（Build 36.1），该区域对应于12.27 Mbp，并且侧翼为标记D4 S2952和D4 S415。在标记D4 S2368处获得的最大两点LOD评分为2.98（θ = 0.00），而在沿着疾病间隔的几个标记处获得的最大多点LOD评分为3.62。在ICNC连锁区间对候选基因进行序列分析，发现一个纯合错义突变（c.577T>C; p.S193P）在编码NAD（+）依赖性15-羟基前列腺素脱氢酶（15-PGDH）的人HPGD基因的外显子6中。15-PGDH在ICNC发病机制中的参与可能为这种酶在指甲形态发生中的功能开辟了有趣的前景。发展
Background: Isolated congenital nail clubbing (ICNC) is a rare autosomal recessive disorder characterised by enlargement of the terminal segments of fingers and toes with thickened nails due to proliferation of the connective tissues and abnormal function of the nail matrix. In the present study, we investigated a large Pakistani family with 11 affected individuals having hereditary congenital nail clubbing as a single invariable clinical feature without any associated ectodermal, skeletal or systemic imperfection.Objective: To identify a gene underlying the ICNC phenotype.Methods: A genome wide homozygosity linkage mapping strategy was used to identify the gene causing ICNC. DNA sequencing was performed to screen 10 candidate genes located in the linkage interval.Results: We assigned the disease locus for the ICNC to a 13.25 cM region on chromosome 4q32.3-q34.1. This region corresponds to 12.27 Mbp according to the sequence based physical map (Build 36.1) and flanked by markers D4S2952 and D4S415. A maximum two point LOD score of 2.98 (theta = 0.00) was obtained at marker D4S2368 while a maximum multipoint LOD score of 3.62 was obtained with several markers along the disease interval. Sequence analysis of the candidate genes, in the ICNC linkage interval, revealed a homozygous missense mutation (c.577T>C; p.S193P) in exon 6 of the human HPGD gene encoding NAD(+) dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).Conclusions: The involvement of 15-PGDH in the pathogenesis of ICNC may open up interesting perspectives into the function of this enzyme in nail morphogenesis/development.