van Reeuwijk Jeroen, Grewal Prabhjit K, Salih Mustafa A M, Beltrán-Valero de Bernabé Daniel, McLaughlan Jenny M, Michielse Caroline B, Herrmann Ralf, Hewitt Jane E, Steinbrecher Alice, Seidahmed Mohamed Z, Shaheed Mohamed M, Abomelha Abdullah, Brunner Han G, van Bokhoven Hans, Voit Thomas
Department of Human Genetics 855, Radboud University Nijmegen Medical Center, Box 9101, 6500 HB Nijmegen, The Netherlands.
Hum Genet. 2007 Jul;121(6):685-90. doi: 10.1007/s00439-007-0362-y. Epub 2007 Apr 14.
Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of alpha-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual alpha-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the alpha-dystroglycan protein.
在肌营养不良（myd）小鼠中，Large基因的基因内纯合缺失与严重的神经肌肉表型相关。这些突变导致α- dystroglycan几乎完全缺乏糖基化。在一名人类患者中报道了复合杂合性LARGE突变，表现为轻度先天性肌营养不良（CMD）和严重智力迟钝。如患者细胞中残留的α- dystroglycan糖基化所示，这些突变可能保留了一些残余的LARGE糖基转移酶活性。我们推测，更严重的LARGE突变与人类更严重的CMD表型相关。在此，我们报道了一个患有沃克-沃尔堡综合征（WWS）的家族中一个63kb的基因内LARGE缺失，该综合征的特征是CMD以及严重的脑和眼结构畸形。这一发现表明，LARGE基因突变可导致广泛的临床谱，这与在α- dystroglycan蛋白翻译后修饰中起作用的其他基因类似。
