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

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

doi:10.1016/j.nmd.2022.08.001

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

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

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 α-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 3^rd confirmed mutation in the DMD gene in Labrador retrievers.

Original language	English (US)
Pages (from-to)	836-841
Number of pages	6
Journal	Neuromuscular Disorders
Volume	32
Issue number	10
DOIs	https://doi.org/10.1016/j.nmd.2022.08.001
State	Published - Oct 2022

Bibliographical note

Funding Information:
SGF is supported in part by an NIH Special Emphasis Research Career Award ( 1 K01 OD027058 ) in Pathology and Comparative Medicine sponsored by the Division of Comparative Medicine, Office of Research Infrastructure Programs. MZ is supported by the Sao Paulo Research Foundation (FAPESP/Brazil) [ 2013/08028-1 , 2014/50931-3 and 2020/09702-1 ] and the National Council for Scientific and Technological Development (CNPq) [ 465355/2014-5 ], and LMK supported in part by the National Institutes of Health R01AR064300 The authors thank Drs. Gena Silver, Nancy Hatfield, Sonnya Denis, and Andrea Molenbeek for searching medical records for clinical information, and the owners of the affected dogs for providing information on final clinical outcomes.

Publisher Copyright:
© 2022

Keywords

Dog
Muscular dystrophy
Myopathy
Whole genome sequencing

Publisher link

10.1016/j.nmd.2022.08.001

Find It

Find It at U of M Libraries

Cite this

@article{69a18564feaa496bb3433ceecfed7b6f,

title = "Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype",

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 α-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{\textquoteright} 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.",

keywords = "Dog, Muscular dystrophy, Myopathy, Whole genome sequencing",

author = "Shelton, {G. Diane} and Minor, {Katie M.} and Vieira, {Natassia M.} and Kunkel, {Louis M.} and Friedenberg, {Steven G.} and Cullen, {Jonah N.} and Guo, {Ling T.} and Mayana Zatz and Mickelson, {James R.}",

note = "Funding Information: SGF is supported in part by an NIH Special Emphasis Research Career Award ( 1 K01 OD027058 ) in Pathology and Comparative Medicine sponsored by the Division of Comparative Medicine, Office of Research Infrastructure Programs. MZ is supported by the Sao Paulo Research Foundation (FAPESP/Brazil) [ 2013/08028-1 , 2014/50931-3 and 2020/09702-1 ] and the National Council for Scientific and Technological Development (CNPq) [ 465355/2014-5 ], and LMK supported in part by the National Institutes of Health R01AR064300 The authors thank Drs. Gena Silver, Nancy Hatfield, Sonnya Denis, and Andrea Molenbeek for searching medical records for clinical information, and the owners of the affected dogs for providing information on final clinical outcomes. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = oct,

doi = "10.1016/j.nmd.2022.08.001",

language = "English (US)",

volume = "32",

pages = "836--841",

journal = "Neuromuscular Disorders",

issn = "0960-8966",

publisher = "Elsevier Limited",

number = "10",

}

TY - JOUR

T1 - Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype

AU - Shelton, G. Diane

AU - Minor, Katie M.

AU - Vieira, Natassia M.

AU - Kunkel, Louis M.

AU - Friedenberg, Steven G.

AU - Cullen, Jonah N.

AU - Guo, Ling T.

AU - Zatz, Mayana

AU - Mickelson, James R.

N1 - Funding Information: SGF is supported in part by an NIH Special Emphasis Research Career Award ( 1 K01 OD027058 ) in Pathology and Comparative Medicine sponsored by the Division of Comparative Medicine, Office of Research Infrastructure Programs. MZ is supported by the Sao Paulo Research Foundation (FAPESP/Brazil) [ 2013/08028-1 , 2014/50931-3 and 2020/09702-1 ] and the National Council for Scientific and Technological Development (CNPq) [ 465355/2014-5 ], and LMK supported in part by the National Institutes of Health R01AR064300 The authors thank Drs. Gena Silver, Nancy Hatfield, Sonnya Denis, and Andrea Molenbeek for searching medical records for clinical information, and the owners of the affected dogs for providing information on final clinical outcomes. Publisher Copyright: © 2022

PY - 2022/10

Y1 - 2022/10

N2 - 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 α-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.

AB - 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 α-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.

KW - Dog

KW - Muscular dystrophy

KW - Myopathy

KW - Whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85136712808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136712808&partnerID=8YFLogxK

U2 - 10.1016/j.nmd.2022.08.001

DO - 10.1016/j.nmd.2022.08.001

M3 - Article

C2 - 36041985

AN - SCOPUS:85136712808

SN - 0960-8966

VL - 32

SP - 836

EP - 841

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 10

ER -

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

Abstract

Bibliographical note

Keywords

Publisher link

Find It

Other files and links

Fingerprint

Cite this