Truncating mutation in the NHS gene:: Phenotypic heterogeneity of Nance-Horan syndrome in an Asian Indian family
Truncating mutation in the NHS gene:: Phenotypic heterogeneity of Nance-Horan syndrome in an Asian Indian family
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DOI：
10.1167/iovs.04-0477
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Kumaramanickavel, G
中科院分区：
文献类型：
--
作者：
Ramprasad, VL;Thool, A;Kumaramanickavel, G
目的.研究了一个四代家系，其中8名受影响的男性，他们遗传了X连锁发育性透镜混浊和小角膜。家族中的一些成员具有提示Nance-Horan综合征的轻度至中度非眼部临床特征。本研究的目的是在一个大型的57个成员的亚洲-印度血统的遗传图谱的基因。通过使用荧光微卫星标记（10-cM间隔）对X染色体进行基于PCR的基因分型。通过使用两种疾病模型进行参数连锁分析，假设通过MLINK/ILINK和FASTLINK（版本4.1P）程序（http：www.hgmp.mrc.ac.uk/;由人类基因组绘图项目资源中心，剑桥，英国在公共领域提供）隐性或显性X连锁传播。在连接区域的NHS基因被筛选用于突变。通过精细定位，将致病基因定位于Xp22.13。多点分析将峰LOD确定为DSX 987处的4.46。NHS基因定位在这个区域。所有受影响的男性和携带者女性（杂合子形式）的突变筛查显示外显子1的截短突变115 C-->T，导致谷氨酰胺转换为终止密码子（Q39 X），但未在未受影响的个体和对照受试者中观察到。一个X连锁Nance-Horan综合征家族有严重的眼部，但轻度至中度的非眼部特征。NHS基因中截短突变（Q39 X）的临床表型表明NHS基因座存在等位基因异质性或存在修饰基因。对于X染色体连锁的白内障家系，应仔细检查眼部和非眼部特征，以排除Nance-Horan综合征。RT-PCR分析没有表明无义介导的mRNA衰减作为临床异质性的可能机制。
PURPOSE. A four-generation family containing eight affected males who inherited X-linked developmental lens opacity and microcornea was studied. Some members in the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. The purpose of the study was to map genetically the gene in the large 57-live-member Asian-Indian pedigree.METHODS. PCR-based genotyping was performed on the X-chromosome, by using fluorescent microsatellite markers (10-cM intervals). Parametric linkage analysis was performed by using two disease models, assuming either recessive or dominant X-linked transmission by the MLINK/ILINK and FASTLINK ( version 4.1P) programs (http:www.hgmp.mrc.ac.uk/;provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK). The NHS gene at the linked region was screened for mutation.RESULTS. By fine mapping, the disease gene was localized to Xp22.13. Multipoint analysis placed the peak LOD of 4.46 at DSX987. The NHS gene mapped to this region. Mutational screening in all the affected males and carrier females ( heterozygous form) revealed a truncating mutation 115C-->T in exon 1, resulting in conversion of glutamine to stop codon (Q39X), but was not observed in unaffected individuals and control subjects.CONCLUSIONS. A family with X-linked Nance-Horan syndrome had severe ocular, but mild to moderate nonocular, features. The clinical phenotype of the truncating mutation ( Q39X) in the NHS gene suggests allelic heterogeneity at the NHS locus or the presence of modifier genes. X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.