Mutations in IMPG1 Cause Vitelliform Macular Dystrophies
Mutations in IMPG1 Cause Vitelliform Macular Dystrophies
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DOI：
10.1016/j.ajhg.2013.07.018
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发表时间：
2013-09-05
影响因子：
9.8
通讯作者：
Hamel, Christian P.
中科院分区：
文献类型：
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作者：
Manes, Gael;Meunier, Isabelle;Hamel, Christian P.
卵黄状黄斑营养不良（VMD）是遗传性视网膜营养不良，其特征在于眼底检查时可见的黄色圆形沉积物，并且在患有青少年Best黄斑营养不良（BMD）或成人发作的卵黄状黄斑营养不良（AVMD）的个体中遇到。尽管许多BMD和一些AVMD病例在BEST 1或PRPH 2中存在突变，但许多受影响的个体的潜在遗传原因仍然未知。在一个常染色体显性VMD大家族中，基因定位和全外显子组测序导致鉴定出c.713T>G（p.Leu238Arg）IMPG 1突变，随后在另外两个常染色体显性VMD家族中发现了相同的表型。IMPG 1编码SPACR蛋白，其是视杆和视锥光感受器细胞外基质结构域的组分。结构建模表明，p.Leu238Arg取代不稳定的保守SEA1结构域的SPACR。对144名患有各种形式黄斑营养不良的先证者进行筛查，发现了另外三种IMPG 1突变。来自一个常染色体隐性VMD家系的两个个体为剪接位点突变c.807+1G>T纯合子，另一个家系的两个个体为突变c.461T>C（p.Leu154Pro）和c.1519C>T（p.A1g507*）复合杂合子。大多数病例的眼电图Arden比率正常或中度降低。我们的结论是IMPG 1突变导致常染色体显性和隐性形式的VMD，从而表明感光细胞间基质的损害可能是VMD的一般原因。
Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.A1g507*). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.