GGPS1Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome
GGPS1Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome
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DOI：
10.1002/ana.25772
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发表时间：
2020-06-18
影响因子：
11.2
通讯作者：
Bonnemann, Carsten G.
中科院分区：
文献类型：
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作者：
Foley, A. Reghan;Zou, Yaqun;Bonnemann, Carsten G.
目的在2名同胞中发现了一种迄今未描述的早发性肌营养不良症的表型，该表型与感音神经性听力损失和原发性卵巢功能不全有关，随后的患者也有类似的表现。本研究的目的是了解这种情况的遗传和分子病因。方法采用全外显子组测序（WES）技术，对5个具有相同表型的家系进行GGPS 1 Sanger测序或WES测序，以确定GGPS 1 Sanger基因的初始双等位基因变异。进行了分子建模、生化分析、激光膜损伤测定和Y259 C基因敲入小鼠的产生。结果6个家系11例患者均携带5种不同的致病基因，GGPS 1编码甲羟戊酸/类异戊二烯途径中的香叶基香叶基二磷酸合酶，催化香叶基香叶基焦磷酸的合成，后者是香叶基香叶基化蛋白质的脂质前体，包括小的鸟苷三磷酸酶。除了近端无力外，所有患者均表现为先天性感音神经性听力损失，所有青春期后女性均表现为原发性卵巢功能不全。肌肉组织学呈营养不良，在最严重的病例中有自噬物质和大线粒体的超微结构证据。激光损伤后，患者来源的肌源性细胞的膜愈合延迟，其中一种突变（Y259 C）的敲入小鼠导致产前死亡。解释特异性GGPS 1突变的鉴定定义了一种独特形式的肌营养不良伴听力损失和卵巢功能不全的病因，并为这种临床星座指出了一种新的途径。ANN NEUROL 2020
Objective A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. Methods We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants inGGPS1followed byGGPS1Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. Results A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains ofGGPS1were identified.GGPS1encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Interpretation The identification of specificGGPS1mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020