TY - JOUR
T1 - Novel mutation in TNPO3 causes congenital limb-girdle myopathy with slow progression
AU - Vihola, Anna
AU - Palmio, Johanna
AU - Danielsson, Olof
AU - Penttilä, Sini
AU - Louiselle, Daniel
AU - Pittman, Sara
AU - Weihl, Conrad
AU - Udd, Bjarne
N1 - Funding Information:
The study was funded by the Finnish Medical Foundation (J.P.), the Academy of Finland (B.U.), the Sigrid Jusélius Foundation (B.U.), and the Folkhälsan Research Foundation (B.U.). This study is not industry sponsored.
Publisher Copyright:
© 2019 American Academy of Neurology.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - ObjectiveWe 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.MethodsPatients 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.ResultsWe 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.ConclusionsWe 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.
AB - ObjectiveWe 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.MethodsPatients 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.ResultsWe 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.ConclusionsWe 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.
UR - http://www.scopus.com/inward/record.url?scp=85068388568&partnerID=8YFLogxK
U2 - 10.1212/NXG.0000000000000337
DO - 10.1212/NXG.0000000000000337
M3 - Article
C2 - 31192305
AN - SCOPUS:85068388568
SN - 2376-7839
VL - 5
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 3
M1 - e337
ER -