A homozygous loss of function variant in POPDC3 : From invalidating exercise intolerance to a limb-girdle muscular dystrophy phenotype
Copyright © 2023 Elsevier B.V. All rights reserved..
Recessive pathogenic variants in POPDC3 have recently been associated with the rare limb-girdle muscular dystrophy (LGMD) subtype LGMDR26. We studied three siblings and a distantly related individual with a skeletal muscle disorder, harboring the c.486-6T>A splice site variant in POPDC3 in homozygosity. Immunohistochemistry, western blot, and mRNA experiments on patients' skeletal muscle tissue as well as on patients' myoblasts were performed to study the pathogenicity of the predicted loss of function mechanism of the variant. Patients mainly presented with invalidating myalgia and exercise intolerance and limited to no segmentary muscle weakness. CK levels were markedly elevated in all patients. A loss of function mechanism at the RNA level was shown (r.485_486insauag, p.Ile163*). Muscle biopsies performed in three out of four patients showed non-specific myopathic features with a marked type 2 fiber predominance and the presence of a large number of severely atrophic fibers with pyknotic nuclear clumps. We show that skeletal muscle symptoms in LGMDR26 may range from an overt late juvenile to young adult-onset limb-girdle muscular dystrophy phenotype to severe exercise intolerance and myalgia, with consistently highly elevated CK levels. We further prove a clear LOF mechanism of POPDC3 in this rare disorder.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:33 |
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| Enthalten in: |
Neuromuscular disorders : NMD - 33(2023), 5 vom: 15. Mai, Seite 432-439 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
De Ridder, Willem [VerfasserIn] |
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| Links: |
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| Themen: |
Cell Adhesion Molecules |
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| Anmerkungen: |
Date Completed 02.06.2023 Date Revised 05.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.nmd.2023.04.003 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35608518X |
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| 100 | 1 | |a De Ridder, Willem |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A homozygous loss of function variant in POPDC3 |b From invalidating exercise intolerance to a limb-girdle muscular dystrophy phenotype |
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| 500 | |a Date Revised 05.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a Recessive pathogenic variants in POPDC3 have recently been associated with the rare limb-girdle muscular dystrophy (LGMD) subtype LGMDR26. We studied three siblings and a distantly related individual with a skeletal muscle disorder, harboring the c.486-6T>A splice site variant in POPDC3 in homozygosity. Immunohistochemistry, western blot, and mRNA experiments on patients' skeletal muscle tissue as well as on patients' myoblasts were performed to study the pathogenicity of the predicted loss of function mechanism of the variant. Patients mainly presented with invalidating myalgia and exercise intolerance and limited to no segmentary muscle weakness. CK levels were markedly elevated in all patients. A loss of function mechanism at the RNA level was shown (r.485_486insauag, p.Ile163*). Muscle biopsies performed in three out of four patients showed non-specific myopathic features with a marked type 2 fiber predominance and the presence of a large number of severely atrophic fibers with pyknotic nuclear clumps. We show that skeletal muscle symptoms in LGMDR26 may range from an overt late juvenile to young adult-onset limb-girdle muscular dystrophy phenotype to severe exercise intolerance and myalgia, with consistently highly elevated CK levels. We further prove a clear LOF mechanism of POPDC3 in this rare disorder | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HyperCKemia | |
| 650 | 4 | |a LGMDR26 | |
| 650 | 4 | |a POPDC3 | |
| 650 | 7 | |a POPDC3 protein, human |2 NLM | |
| 650 | 7 | |a Muscle Proteins |2 NLM | |
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| 700 | 1 | |a de Vries, Geert |e verfasserin |4 aut | |
| 700 | 1 | |a Van Schil, Kristof |e verfasserin |4 aut | |
| 700 | 1 | |a Deconinck, Tine |e verfasserin |4 aut | |
| 700 | 1 | |a Mouly, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Straub, Volker |e verfasserin |4 aut | |
| 700 | 1 | |a Baets, Jonathan |e verfasserin |4 aut | |
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