A novel point mutation affecting Asn76 of dystrophin protein leads to dystrophinopathy

•Missense mutations are rare cause of Duchenne/Becker muscular dystrophy.•Confirmatory testing of single-exon deletions detected by MLPA is important.•We describe a novel missense mutation in the DMD gene.•To predict the severity is challenging at young age in case of a new mutation. Mutations in th...

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Published in:Neuromuscular disorders : NMD 2018-02, Vol.28 (2), p.129-136
Main Authors: Koczok, Katalin, Merő, Gabriella, Szabó, Gabriella P., Madar, László, Gombos, Éva, Ajzner, Éva, Mótyán, János András, Hortobágyi, Tibor, Balogh, István
Format: Article
Language:English
Subjects:
Duchenne/Becker muscular dystrophy
Dystrophin
Dystrophinopathy
MLPA
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Summary:•Missense mutations are rare cause of Duchenne/Becker muscular dystrophy.•Confirmatory testing of single-exon deletions detected by MLPA is important.•We describe a novel missense mutation in the DMD gene.•To predict the severity is challenging at young age in case of a new mutation. Mutations in the DMD gene lead to Duchenne and Becker muscular dystrophy (DMD/BMD). Missense mutations are rare cause of DMD/BMD. A six-month-old male patient presented with mild generalized muscle weakness, hypotonia, and delayed motor development. Dystrophinopathy was suspected because of highly elevated serum creatine kinase level (1497 U/L) and tiered DMD gene analysis was performed. Multiplex ligation-dependent probe amplification (MLPA) assay showed deletion of exon 4, which could not be confirmed by another method. Sequencing of exon 4 revealed a novel de novo point mutation (c.227A>T, p.Asn76Ile) in the N-terminal actin-binding domain (N-ABD) of dystrophin protein. The false positive MLPA result was explained by the fact that the affected nucleotide lies directly at the 3' ligation site of the MLPA probe. Sequencing of the whole coding region of DMD gene proved c.227A>T to be the sole variant being potentially pathogenic. According to in silico analyses the mutation was predicted to be highly destabilizing on N-ABD structure possibly leading to protein malfunction. Muscle biopsy was performed and dystrophin immunohistochemistry results were suggestive of BMD. Our results highlight the importance of confirmatory testing of single-exon deletions detected by MLPA and we describe a novel, destabilizing missense mutation in the DMD gene.
ISSN:0960-8966
1873-2364
DOI:10.1016/j.nmd.2017.12.003