Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy
Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy
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DOI：
10.1016/j.ajhg.2014.07.007
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发表时间：
2014-08-07
影响因子：
9.8
通讯作者：
Doherty, Dan
中科院分区：
文献类型：
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作者：
Aldinger, Kimberly A.;Mosca, Stephen J.;Doherty, Dan
小脑发育不良伴囊肿(CDC)是一种典型的影像表现，常合并鹅卵石皮质和先天性肌营养不良。最近，报告了7例无神经肌肉受累(Poretti-Boltshauser综合征)的儿童的CDC。结合纯合子作图和全外显子测序，我们确定LAM41双等位基因突变是7名患者(来自5个家系)CDC的原因，与Poretti-Boltshauser综合征的表型描述中的那些无关。这些人中的大多数也有高度近视，一些人有视网膜营养不良和皮质白质中斑片状T2加权液体衰减反转恢复(T2/FLAIR)信号。在另外一个家族中，我们发现了两个兄弟姐妹，他们有截短的LAMA1突变，并伴有视网膜营养不良和无囊肿的轻度小脑发育不良，表明囊肿不是与LAMA1功能丧失相关的必备特征。这项工作扩大了与椎板病变相关的表型谱，并强调了不同的层粘连蛋白编码基因所起的组织特异性作用。
Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAM41 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.