Krag Thomas, Nasho Emily, Brady Lauren, Verebi Camille, Leturcq France, Malfatti Edoardo, Duno Morten, Tarnopolsky Mark, Vissing John
Copenhagen Neuromuscular Center, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Neuromuscular and Neurometabolic Clinic, McMaster University Medical Centre, Hamilton, Canada.
Hum Mutat. 2025 Mar 29;2025:9301465. doi: 10.1155/humu/9301465. eCollection 2025.
Limb-girdle muscular dystrophy Type 2A/R1 or calpain-3 deficiency is the most common autosomal recessive limb-girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain-3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain-3 gene in mildly to moderately affected patients with limb-girdle muscular dystrophy without biallelic gene variants in . Here, we report four cases with creatine kinase levels above 1500 U/L, mild-to-moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the variant c.304C>T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in . The third and fourth patients were heterozygous for c.1371C>G; p.(Asn457Lys) and c.1490C>T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near-complete loss of calpain-3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild-to-moderate proximal weakness, increased level of creatine kinase, and near-complete loss of calpain-3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain-3. This information could aid in determining whether a variant of unknown significance is pathological.
2A型/ R1型肢带型肌营养不良症或钙蛋白酶-3缺乏症是最常见的常染色体隐性肢带型肌营养不良症。然而，近年来，已报道了常染色体显性病例以及钙蛋白酶-3缺乏的家族，并且对于在没有双等位基因变异的轻度至中度受影响的肢带型肌营养不良症患者中寻找钙蛋白酶-3基因的单变异体产生了新的兴趣。在此，我们报告了4例肌酸激酶水平高于1500 U/L、轻度至中度近端肌无力、鸭步和肩胛翼状肩胛的病例。两名患者，一名儿子及其父亲，对于变异体c.304C>T；p.(Pro102Ser)呈杂合状态，该变异体先前已在具有复合杂合变异体的患者中报道过。第三和第四例患者分别对于c.1371C>G；p.(Asn457Lys)和c.1490C>T；p.Ala497_Glu508del呈杂合状态，之前均未报道过。通过蛋白质免疫印迹法测定，所有4例患者的钙蛋白酶-3几乎完全缺失。虽然遗传性常染色体显性钙蛋白酶病现已得到明确证实，但可能会出现更多显性钙蛋白酶病的单病例；一些病例会与父母或兄弟姐妹的临床表现相关，而另一些则会源于自发突变，但受影响个体仍具有类似的临床表现，即轻度至中度近端肌无力、肌酸激酶水平升高以及钙蛋白酶-3蛋白几乎完全缺失。本报告将已知导致显性钙蛋白酶病的变异体数量从8个增加到11个，这些变异体似乎仅存在于构成钙蛋白酶-3的四个结构域中的两个结构域中。这一信息有助于确定意义不明的变异体是否具有致病性。
