title: A novel mutation in the PDZ-like motif of ZASP causes distal ZASP-related myofibrillar myopathy.
abstract: Mutations in the LDB3 gene have been identified in patients with Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP)-related myofibrillar myopathy (ZASP-MFM) characterized by late-onset distal myopathy with signs of cardiomyopathy and neuropathy. We describe an autosomal dominant inherited pedigree with ZASP-MFM that is in line with the typical phenotype of distal myopathy without cardiomyopathy and neuropathy, while mild asymmetrical muscle atrophy can be observed in some affected members. Muscle MRI revealed considerable fatty degeneration involved in the posterior compartment of thigh and lower leg, but relatively preserved in rectus femoris, sartorius, gracilis, adductor longus and biceps femoris breve muscles in the later stage. In addition, fatty infiltration of medial gastrocnemius muscle can be initiated as early as in the third decade in asymptomatic individuals. Myopathological features showed sarcoplasmic accumulation of multiple protein deposits and electron dense filamentous bundle aggregates. A novel heterozygous missense mutation (p.N155H) in a highly conserved PDZ-like motif of ZASP was identified. The results indicate that typical ZASP-MFM presenting with late-onset distal myopathy is commonly associated with mutations in PDZ-like motif of ZASP. The development of fatty degeneration is consistent with the typical pattern of ZASP-MFM, and the initial fatty infiltration might be started from medial gastrocnemius muscle. Our study expands the clinical and mutational spectrum of ZASP-MFM.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Daojun
authors.initials: D
authors.lastname: Hong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000473:pathology*; D009133:Muscular Atrophy / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D009136:Muscular Dystrophies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120696:LDB3 protein, human; D060588:LIM Domain Proteins
keywords: LDB3; ZASP; distal myopathy; muscle MRI; myofibrillar myopathy