Yonsei Med J.  2016 Jan;57(1):173-179. 10.3349/ymj.2016.57.1.173.

Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

• Park HJ
• Jang H
• Lee JH
• Shin HY
• Cho SR
• Park KD
• Bang D
• Lee MG
• Kim SM
• Lee JH
• Choi YC

• KMID: 2466367
• DOI: http://doi.org/10.3349/ymj.2016.57.1.173

Abstract

PURPOSE
This study was designed to investigate the characteristics of Korean patients with calpainopathy.
MATERIALS AND METHODS
Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed.
RESULTS
Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology.
CONCLUSION
We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.

Keyword

Limb girdle muscular dystrophy 2A; calpainopathy; CAPN3; lobulated fiber; genetic testing

MeSH Terms

Adolescent
Adult
Amino Acid Sequence
Asian Continental Ancestry Group/*genetics
Calpain/*genetics
Female
Genetic Testing
Humans
Male
Molecular Sequence Data
Muscle Proteins/*genetics
Muscle, Skeletal/pathology
Muscular Dystrophies, Limb-Girdle/ethnology/*genetics/*pathology
*Mutation
Republic of Korea
Calpain
Muscle Proteins

Figure

• 

  Fig. 1 Pedigrees and localizations of different CAPN3 mutations in Korean families with calpainopathy. (A) Pedigrees of 10 Korean families with CAPN3 mutations. Asterisks (*) indicate individuals whose DNA was used for sequencing. (B) Schematic representation of calpain 3 protein (NM_000070). Domain II is a cysteine protease domain, and domain IV is a calcium-binding domain. Muscle-specific sequences of calpain 3 at the N-terminal domain I (NS), protease domain II (IS1), and between domains III and IV (IS2). Black dots (●), numbers of alleles with mutations; dagger (†), four novel mutations.

• 

  Fig. 2 Calpain-3 band pattern on western blot. Western blot for calpain-3 revealed normal expression in the F4 patient yet nearly total loss in six other patients.

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  Fig. 3 Pathologic findings of F7 patients. (A) Fiber-size variation and increased endomysial fibrosis on hematoxylin and eosin staining. (B) A small number of degenerative muscle fibers (▪) on modified Gomori trichrome staining. (C and D) A small number of lobulated fibers (*) after staining with nicotinamide adenine dinucleotide tetrazolium reductase.

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