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Gene. 2019 May 20;697:159-164. doi: 10.1016/j.gene.2019.02.011. Epub 2019 Feb 19.

Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene.

Author information

1
Medical Genetics Laboratory, Petrovsky Russian Research Center of Surgery, Moscow 119991, Russia. Electronic address: julia.rogozhina@gmail.com.
2
Laboratory of Functional Genomics, Research Centre for Medical Genetics, Moscow 115522, Russia.
3
Medical Genetics Laboratory, Petrovsky Russian Research Center of Surgery, Moscow 119991, Russia.
4
Laboratory of Functional Genomics, Research Centre for Medical Genetics, Moscow 115522, Russia; School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia.
5
Medical Genetics Laboratory, Petrovsky Russian Research Center of Surgery, Moscow 119991, Russia; Pirogov Russian National Research Medical University, Moscow 117997, Russia.

Abstract

Mutations in the MYH7 gene are the source of an allelic series of diseases, including various cardiomyopathies and skeletal myopathies that usually manifest in adulthood. We observed a 1.5 y.o. male patient with congenital weaknesses of the axial muscles, "dropped head" syndrome, and dilated cardiomyopathy. The clinical evaluation included medical history, an echocardiogram, electromyography, and a histopathological study. The genetic evaluation included whole exome sequencing. Muscle biopsy samples from the proband were used for mRNA extraction. We revealed a novel genetic variant c.5655 + 5G > C in the MYH7 gene. The analysis of the cDNA showed an in-frame skipping of exon 38 (p.1854_1885del). This variant and two previously published mutations (c.5655G > A and c.5655 + 1G > A), also presumably leading to exon 38 skipping, were studied by expression analysis in the HEK293T cell line transfected with 4 plasmids containing the MYH7 minigene (wt, c.5655G > C, c.5655 + 1G > A and c.5655 + 5G > A). A quantitative difference in expression was shown for cell lines with each of the three mutant plasmids. All mutation carriers had a similar phenotype and included congenital axial myopathy and variable cardiac involvement. Prominent dropped head syndrome was mentioned in all patients. Early-onset axial myopathy with a dropped head syndrome is a distinct clinical entity within MYH7-related disorders. We suggest that mutations in the MYH7 gene affecting the C-terminal domain of beta-myosin heavy chain should also be considered as a possible cause in cases of early-onset myopathy with "dropped head" syndrome.

KEYWORDS:

Congenital myopathy; Dilated cardiomyopathy; Dropped head syndrome; Exon-skipping; Floppy head syndrome; MYH7; MYH7-related myopathy; Splicing

PMID:
30794915
DOI:
10.1016/j.gene.2019.02.011
[Indexed for MEDLINE]

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