A Mutation in MTM1 Causes X-Linked Myotubular Myopathy in Boykin Spaniels

Overview

Journal Neuromuscul Disord

Specialty Neurology

Date 2020 May 18

PMID 32417001

Citations 4

Authors

Natasha J Olby

Steven Friedenberg

Kathryn Meurs

Dylan Deprospero

Julien Guevar

Jeanie Lau

Oriana Yost

Ling T Guo

G Diane Shelton

Affiliations

Soon will be listed here.

Abstract

The purpose of this study was to report the findings of clinical and genetic evaluation of a 3-month old male Boykin spaniel (the proband) that presented with progressive weakness. The puppy underwent a physical and neurological examination, serum biochemistry and complete blood cell count, electrophysiological testing, muscle biopsy and whole genome sequencing. Clinical evaluation revealed generalized neuromuscular weakness with tetraparesis and difficulty holding the head up and a dropped jaw. There was diffuse spontaneous activity on electromyography, most severe in the cervical musculature. Nerve conduction studies were normal, the findings were interpreted as consistent with a myopathy. Skeletal muscle was grossly abnormal on biopsy and there were necklace fibers and abnormal triad structure localization on histopathology, consistent with myotubular myopathy. Whole genome sequencing revealed a premature stop codon in exon 13 of MTM1 (ChrX: 118,903,496 C > T, c.1467C>T, p.Arg512X). The puppy was humanely euthanized at 5 months of age. The puppy's dam was heterozygous for the variant, and 3 male puppies from a subsequent litter all of which died by 2 weeks of age were hemizygous for the variant. This naturally occurring mutation in Boykin spaniels causes a severe form of X-linked myotubular myopathy, comparable to the human counterpart.

Citing Articles

Whole Animal Genome Sequencing: user-friendly, rapid, containerized pipelines for processing, variant discovery, and annotation of short-read whole genome sequencing data.

Cullen J, Friedenberg S G3 (Bethesda). 2023; 13(8).

PMID: 37243692 PMC: 10411559. DOI: 10.1093/g3journal/jkad117.

X-linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat.

Kopke M, Shelton G, Lyons L, Wall M, Pemberton S, Gedye K J Vet Intern Med. 2022; 36(5):1800-1805.

PMID: 35962713 PMC: 9511081. DOI: 10.1111/jvim.16509.

A dog model for centronuclear myopathy carrying the most common DNM2 mutation.

Bohm J, Barthelemy I, Landwerlin C, Blanchard-Gutton N, Relaix F, Blot S Dis Model Mech. 2022; 15(4).

PMID: 35244154 PMC: 9016898. DOI: 10.1242/dmm.049219.

Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies.

Djeddi S, Reiss D, Menuet A, Freismuth S, de Carvalho Neves J, Djerroud S Mol Ther. 2021; 29(8):2514-2534.

PMID: 33940157 PMC: 8353243. DOI: 10.1016/j.ymthe.2021.04.033.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Nance J, Dowling J, Gibbs E, Bonnemann C . Congenital myopathies: an update. Curr Neurol Neurosci Rep. 2012; 12(2):165-74. PMC: 4491488. DOI: 10.1007/s11910-012-0255-x. View

Wang S, Li W, Liu S, Xu J . RaptorX-Property: a web server for protein structure property prediction. Nucleic Acids Res. 2016; 44(W1):W430-5. PMC: 4987890. DOI: 10.1093/nar/gkw306. View

Lindblad-Toh K, Wade C, Mikkelsen T, Karlsson E, Jaffe D, Kamal M . Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005; 438(7069):803-19. DOI: 10.1038/nature04338. View

Doerks T, Strauss M, Brendel M, Bork P . GRAM, a novel domain in glucosyltransferases, myotubularins and other putative membrane-associated proteins. Trends Biochem Sci. 2000; 25(10):483-5. DOI: 10.1016/s0968-0004(00)01664-9. View

Beggs A, Bohm J, Snead E, Kozlowski M, Maurer M, Minor K . MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc Natl Acad Sci U S A. 2010; 107(33):14697-702. PMC: 2930454. DOI: 10.1073/pnas.1003677107. View

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View

Buj-Bello A, Biancalana V, Moutou C, Laporte J, Mandel J . Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy. Hum Mutat. 1999; 14(4):320-5. DOI: 10.1002/(SICI)1098-1004(199910)14:4<320::AID-HUMU7>3.0.CO;2-O. View

McEntagart M, Parsons G, Buj-Bello A, Biancalana V, Fenton I, Little M . Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord. 2002; 12(10):939-46. DOI: 10.1016/s0960-8966(02)00153-0. View

10.

Cosford K, Taylor S, Thompson L, Shelton G . A possible new inherited myopathy in a young Labrador retriever. Can Vet J. 2008; 49(4):393-7. PMC: 2275345. View

11.

Oliveira J, Oliveira M, Kress W, Taipa R, Melo Pires M, Hilbert P . Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database. Eur J Hum Genet. 2012; 21(5):540-9. PMC: 3641378. DOI: 10.1038/ejhg.2012.201. View

12.

Shelton G, Rider B, Child G, Tzannes S, Guo L, Moghadaszadeh B . X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1 gene. Skelet Muscle. 2015; 5(1):1. PMC: 4320619. DOI: 10.1186/s13395-014-0025-3. View

13.

Buj-Bello A, Laugel V, Messaddeq N, Zahreddine H, Laporte J, Pellissier J . The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci U S A. 2002; 99(23):15060-5. PMC: 524320. DOI: 10.1073/pnas.212498399. View

14.

Walmsley G, Blot S, Venner K, Sewry C, Laporte J, Blondelle J . Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems. Am J Pathol. 2016; 187(2):441-456. DOI: 10.1016/j.ajpath.2016.10.002. View

15.

Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C . T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci U S A. 2009; 106(44):18763-8. PMC: 2773964. DOI: 10.1073/pnas.0900705106. View

16.

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

17.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

18.

Laporte J, Hu L, Kretz C, Mandel J, Kioschis P, Coy J . A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet. 1996; 13(2):175-82. DOI: 10.1038/ng0696-175. View

19.

Laporte J, Blondeau F, Gansmuller A, Lutz Y, Vonesch J, Mandel J . The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane ruffles. J Cell Sci. 2002; 115(Pt 15):3105-17. DOI: 10.1242/jcs.115.15.3105. View

20.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View