Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death
Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death
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DOI：
10.1002/mgg3.181
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发表时间：
2016-01-01
影响因子：
2
通讯作者：
Lewis, Richard A.
中科院分区：
文献类型：
--
作者：
Boone, Philip M.;Yuan, Bo;Lewis, Richard A.
背景青少年发病的白内障是已知的Hutterites之间的北美。尽管被确定超过30年前，这种常染色体隐性遗传的条件还没有被映射，和疾病的基因是unknow.MethodsWe进行了全外显子组测序的三个哈特型白内障三重奏和后续的基因分型和映射在四个扩展kinetic.ResultsTrio外显子组使全基因组的纯合性映射，将疾病基因定位到染色体6p上的9.5 Mb区域。该区域含有两个候选变体，LEMD 2 c.T38G和MUC 21 c.665delC。扩展家系招募变异基因分型显示多个额外的亲属与青少年发病的白内障，以及6个已故的亲属与白内障和心脏性猝死。在84个家族成员中对候选变体进行基因分型，包括17个白内障患者;仅LEMD 2中的变体与白内障共分离（LOD = 9.62）。9.5 Mb连锁区域内基于SNP的精细定位通过将白内障基因座细化到含有LEMD 2但不含MUC 21的0.5- 2.9 Mb亚区（6p21.32-p21.31）来支持这一发现。LEMD 2在小鼠和人类晶状体中表达，并编码一个含LEM结构域的蛋白质;预测c.T38G错义突变会使该结构域内的一个高度保守的残基发生突变（p.Leu13Arg）.ConclusionWe进行了哈特型白内障的遗传和基因组研究，发现了这种表型与心脏性猝死相关的证据。使用遗传学和基因组学相结合的方法，我们将白内障映射到6号染色体的一小部分，并提出它们是由LEMD 2中的纯合错义突变引起的。
BackgroundJuvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.MethodsWe performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.ResultsTrio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).ConclusionWe performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.