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

TitleLimb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations
Authors
Issue Date2017
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ejhg
Citation
European Journal of Human Genetics, 2017, v. 25 n. 2, p. 192-199 How to Cite?
AbstractThough 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. © 2017 Macmillan Publishers Limited. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/275190
ISSN
2019 Impact Factor: 3.657
2015 SCImago Journal Rankings: 2.077
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLam, CW-
dc.contributor.authorWong, KS-
dc.contributor.authorLeung, HW-
dc.contributor.authorLaw, CY-
dc.date.accessioned2019-09-10T02:37:25Z-
dc.date.available2019-09-10T02:37:25Z-
dc.date.issued2017-
dc.identifier.citationEuropean Journal of Human Genetics, 2017, v. 25 n. 2, p. 192-199-
dc.identifier.issn1018-4813-
dc.identifier.urihttp://hdl.handle.net/10722/275190-
dc.description.abstractThough 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. © 2017 Macmillan Publishers Limited. All rights reserved.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ejhg-
dc.relation.ispartofEuropean Journal of Human Genetics-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]-
dc.titleLimb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations-
dc.typeArticle-
dc.identifier.emailLam, CW: ching-wanlam@pathology.hku.hk-
dc.identifier.authorityLam, CW=rp00260-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/ejhg.2016.162-
dc.identifier.pmid27966543-
dc.identifier.scopuseid_2-s2.0-85006275584-
dc.identifier.hkuros303489-
dc.identifier.volume25-
dc.identifier.issue2-
dc.identifier.spage192-
dc.identifier.epage199-
dc.identifier.isiWOS:000394122900011-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1018-4813-

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