Heterozygous CAPN3 missense variants causing autosomal‐dominant calpainopathy in seven unrelated families,Neuropathology and Applied Neurobiology

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Heterozygous CAPN3 missense variants causing autosomal‐dominant calpainopathy in seven unrelated families
Neuropathology and Applied Neurobiology ( IF 4.0 ) Pub Date : 2020-09-28 , DOI: 10.1111/nan.12663
L González-Mera _{1,

2} , G Ravenscroft ₃ , M Cabrera-Serrano _{3,

4,

5,

6} , N Ermolova ₇ , C Domínguez-González ₈ , A Arteche-López ₉ , P Soltanzadeh ₁₀ , F Evesson _{11,

12} , C Navas ₁ , F Mavillard _{5,

6} , J Clayton ₃ , P Rodrigo _{1,

2} , E Servián-Morilla _{4,

5,

6} , S T Cooper _{11,

12,

13} , L Waddell _{11,

13} , K Reardon ₁₄ , A Corbett ₁₅ , A Hernandez-Laín ₁₆ , A Sanchez ₁₇ , J Esteban Perez ₈ , C Paradas-Lopez _{4,

5,

6} , E Rivas-Infante _{6,

18} , M Spencer ₁₉ , N Laing ₃ , M Olivé _{1,

2}

Affiliation

Neuropathology Unit, Department of Pathology, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, WA, Australia.
Neurology Department, Hospital Universitario Virgen del Rocío, Seville, Spain.
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocıo/CSIC, Universidad de Sevilla, Sevilla, Spain.
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Neuromuscular Unit, Department of Neurology, Hospital Universitario 12 de Octubre, Research Institute imas12, Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
Department of Genetic, Hospital Universitario 12 de Octubre, Madrid, Spain.
Departments of Neurology and Physiology, David Geffen School of Medicine, UCLA, University of California, Los Angeles, CA, USA.
Kids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW, Australia.
The Children's Medical Research Institute, Westmead, NSW, Australia.
Discipline of Child and Adolescent Health, Faculty of Health and Medicine, University of Sydney, Westmead, NSW, Australia.
St. Vincent's Melbourne Neuromuscular Diagnostic Laboratory, Department of Clinical Neurosciences and Neurological Research, St Vincent's Hospital, Melbourne, VIC, Australia.
Department of Neurology, Concord General Repatriation Hospital, Sydney, NSW, Australia.
Department of Pathology, Neuropathology Unit. Hospital Universitario 12 de Octubre, Madrid, Spain.
Institut de Diagnòstic per la imatge (IDI), IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Department of Neuropathology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Department of Neurology, Neuromuscular Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

AIMS Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from 7 unrelated families. RESULTS The c.700G>A, [p.(Gly234Arg)], c.1327T>C [p.(Ser443Pro], c.1333G>A [p.(Gly445Arg)], c.1661A>C [p.(Tyr554Ser)] and c.1706T>C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh, and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction of calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

中文翻译：

导致七个不相关家族中常染色体显性钙蛋白酶病的杂合 CAPN3 错义变异

AIMS CAPN3 基因中的隐性变异是常染色体隐性肢带肌营养不良最常见形式的原因。然而，CAPN3 中的两个不同的框内缺失（NM_000070.3:c.643_663del21 和 c.598_621del15）以及最近的 Gly445Arg 和 Arg572Pro 替换与常染色体显性 (AD) 形式的钙痛病有关。我们报告了来自 7 个不相关家族的 21 名受影响个体，他们在 CAPN 方法中表现出常染色体显性遗传的肌营养不良症，与五种不同的杂合错义变异相关：我们使用大规模平行基因测序 (MPS) 来确定显性肢体形式的遗传基础来自 7 个无关家庭的受影响个体的带状肌营养不良症。结果 c.700G>A, [p.(Gly234Arg)], c.1327T>C [p.(Ser443Pro], c.1333G>A [p.(Gly445Arg)], c.1661A> 鉴定了 C [p.(Tyr554Ser)] 和 c.1706T>C [p.(Phe569Ser)] CAPN3 变体。受影响的个体在青年期出现进行性近端和轴向无力、蹒跚行走和肩胛骨翼或孤立的高血钾。肌肉成像显示椎旁肌肉脂肪替代，臀肌和大腿后隔室不同程度的受累，以及腿部中部水平的轻微变化。肌肉活检显示轻度肌病变化。蛋白质印迹分析显示相对于对照，骨骼肌中的钙蛋白酶 3 明显减少。根据钙蛋白酶 3 的预测结构对这些变体进行蛋白质建模显示，所有变体都位于钙调蛋白结合位点附近，预计会干扰蛋白水解激活。

更新日期：2020-09-28

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