Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations

Abstract

Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing. A 20 MB-region of homozygosity (ROH) was mapped on chromosome 6q15-21. This was the only ROH that present in all clinically affected siblings and absent in all clinically unaffected siblings. WES showed a novel variant of AK9 gene located in this ROH. This variant was a start-gain mutation and introduced a cryptic 5′-UTR signal in intron 5 of the AK9 gene. The normal splicing signal would be interfered by the cryptic translation signal leading to defective splicing. Another 25 MB-ROH was found on chromosome 11p13-q12 in all siblings. WES showed a homozygous RAPSN pathogenic variant in this ROH. Since RAPSN-associated limb-girdle type CMS was only manifested in AK9 homozygous variant carriers, the disease phenotype was of digenic inheritance, and was determined by the novel disease modifier AK9 which provides NTPs for N-glycosylation. This is the first time that this specific genotype-phenotype correlation is reported. Importantly, the AK9-associated nucleotide deficiency may replete by dietary supplements. Since AK9 is a disease modifier, enhancing N-glycosylation by increasing dietary nucleotides may be a new therapeutic option for CMS patients.

Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

“…Moreover, in some cases, mutations in more than one gene could be necessary to cause the disease [ 42 ]. Thus, digenic inheritance has been proven for a subtype of facioscapulohumeral muscular dystrophy [ 43 ] found in congenital myasthenic syndrome [ 44 ], and it has also been suggested for calpainopathy [ 45 ].…”

<p>The Association Between RAPSN Methylation in Peripheral Blood and Early Stage Lung Cancer Detected in Case–Control Cohort</p>

“…Lam et al reported that defective of AK9 reduces N-glycosylation of AChR and rapsyn while a defective RAPSN impairs the clustering of AChR. 38 Thus, we speculated RAPSN and the methylation of RAPSN connected with LC through CDK5 by cell cycle and AK9 by N-glycosylation pathway. Still, the specify molecular mechanism of RAPSN methylation and LC might be a topic for further studies as well.…”

Myofibrillar myopathy in the genomic context

“…On the other hand, typical digenic inheritance has been demonstrated in facioscapulohumeral muscular dystrophy (Lemmers et al 2012), in congenital myasthenic syndrome (Lam et al 2017), and in calpainopathy (Sáenz and accumulation of seemingly benign variants, including both mutations and polymorphisms, can lead to disease. In c and d, variants cause partial defects either in one pathway or in intersecting pathways, which together produce a cumulative effect leading to the disease.…”