TY - JOUR
T1 - Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy
AU - Undiagnosed Diseases Network
AU - Donkervoort, Sandra
AU - Mohassel, Payam
AU - O'Leary, Melanie
AU - Bonner, Devon E.
AU - Hartley, Taila
AU - Acquaye, Nicole
AU - Brull, Astrid
AU - Mozaffar, Tahseen
AU - Saporta, Mario A.
AU - Dyment, David A.
AU - Sampson, Jacinda B.
AU - Pajusalu, Sander
AU - Austin-Tse, Christina
AU - Hurth, Kyle
AU - Cohen, Julie S.
AU - McWalter, Kirsty
AU - Warman-Chardon, Jodi
AU - Crunk, Amy
AU - Foley, A. Reghan
AU - Acosta, Maria T.
AU - Adams, David R.
AU - Alvarez, Raquel L.
AU - Alvey, Justin
AU - Allworth, Aimee
AU - Andrews, Ashley
AU - Ashley, Euan A.
AU - Afzali, Ben
AU - Bacino, Carlos A.
AU - Bademci, Guney
AU - Balasubramanyam, Ashok
AU - Baldridge, Dustin
AU - Bale, Jim
AU - Bamshad, Michael
AU - Barbouth, Deborah
AU - Bayrak-Toydemir, Pinar
AU - Beck, Anita
AU - Beggs, Alan H.
AU - Behrens, Edward
AU - Bejerano, Gill
AU - Bellen, Hugo J.
AU - Bennett, Jimmy
AU - Bernstein, Jonathan A.
AU - Berry, Gerard T.
AU - Bican, Anna
AU - Bivona, Stephanie
AU - Blue, Elizabeth
AU - Bohnsack, John
AU - Bonner, Devon
AU - Botto, Lorenzo
AU - Izumi, Kosuke
N1 - Publisher Copyright:
© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
PY - 2024/3
Y1 - 2024/3
N2 - Objective: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. Methods: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. Results: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. Interpretation: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.
AB - Objective: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. Methods: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. Results: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. Interpretation: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.
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U2 - 10.1002/acn3.51983
DO - 10.1002/acn3.51983
M3 - Article
C2 - 38311799
AN - SCOPUS:85184683092
SN - 2328-9503
VL - 11
SP - 629
EP - 640
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 3
ER -