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Novel mutation in TNPO3 causes congenital limb-girdle myopathy with slow progression
Univ Helsinki, Finland.
Tampere Univ, Finland; Univ Hosp Tampere, Finland.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
Univ Hosp Tampere, Finland; Tampere Univ, Finland.
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2019 (English)In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 5, no 3, article id UNSP e337Article in journal (Refereed) Published
Abstract [en]

Objective We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. Methods Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. Results We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. Conclusions We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2019. Vol. 5, no 3, article id UNSP e337
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-160065DOI: 10.1212/NXG.0000000000000337ISI: 000481667200013PubMedID: 31192305OAI: oai:DiVA.org:liu-160065DiVA, id: diva2:1349017
Note

Funding Agencies|Finnish Medical Foundation; Academy of Finland; Sigrid Juselius Foundation; Folkhalsan Research Foundation

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-09-06

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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Neurology
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