Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype

Author(s)

Shelton, G. Diane ; Minor, Katie M. ; Vieira, Natassia M. ; Kunkel, Louis M. ; Friedenberg, Steven G. ; Cullen, Jonah N. ; Guo, Ling T. ; Zatz, Mayana ; Mickelson, James R.

• Document type: Journal article
• Source: Neuromuscular Disorders; v. 32, n. 10, p. 6-pg., 2022-10-27.

Abstract

A form of dystrophinopathy with mild or subclinical neuromuscular signs has been previously reported in a family of Labrador retrievers. Markedly and persistently elevated creatine kinase activity was first noted at 6 months of age. Skeletal muscle biopsies revealed a dystrophic phenotype, with dystrophin non-detectable on western blotting and immunohistochemical staining, and with increased utrophin expression. In this report we demonstrate with western blotting that alpha-dystroglycan is present at essentially normal levels. Whole genome sequencing has also now revealed an approximately 400kb tandem genomic DNA duplication including exons 2-7 of the DMD gene that was inserted into intron 7 of the wild type gene. Skeletal muscle cDNA from 2 cases contained DMD transcripts as expected from an in-frame properly-spliced exon 2-7 tandem insertion. A similar 5' duplication involving DMD exons 2-7 has been reported in a human family with dilated cardiomyopathy but without skeletal myopathy. This is the 3rd confirmed mutation in the DMD gene in Labrador retrievers. (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/50931-3 - Aging and genetic disorders: genomics and metagenomics
• Grantee: Mayana Zatz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/09702-1 - Study of protective genetic variants in resilient nonagenarians and centenarians
• Grantee: Mateus Vidigal de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral