营养不良症(α-DG)是一种相对常见的疾病,与低糖基化α-营养不良相关的先天性肌营养不良(CMD)和肢带肌营养不良(LGMD)的临床和遗传异质性类别。迄今为止,至少19个基因的突变与α-DG相关。其中一个,GMPPB,编码鸟苷-二磷酸-甘露糖(GDP-甘露糖)焦磷酸化酶B蛋白,最近与广泛的临床范围有关,从严重的Walker-Warburg综合征到假代谢性肌病,甚至先天性肌无力综合征。我们对73名意大利患者的全套已知疾病基因进行了重新测序,并有证据表明α-营养不良聚糖减少或几乎不存在,以评估该队列中的基因型-表型相关性。我们使用创新的生物信息学工具来计算所有描述的GMPPB突变对蛋白质功能的影响,并试图将它们与表型表达相关联。
我们从12个家族中鉴定出另外13个病例,并定义了7个新的突变。患者表现出可变的表型,包括不太典型的图片,从无症状的高CK血症,出生时关节发育不良和先天性马蹄内翻足,还表现出神经发育合并症,如癫痫发作和共济失调步态,以及自闭症谱系障碍,这在临床报道中很少描述。我们还证明,意大利GMPPB突变人群中很少发生突变,并且蛋白质稳定性的改变是GMPPB错义变体的主要作用。
这项工作增加了α-DG中基因型-表型相关性的数据,并提供了新的生物学工具,以提供理解这些疾病复杂性所需的概念框架。
Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions.
We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of
dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants.
This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.