Myotonic dystrophy is characterized by considerable variability in signs and symptoms that involve multiple body systems. In addition to variations resulting from repeat length and tissue-specific somatic repeat expansions, we know that gender can influence disease phenotype. Yet, there is a general lack of understanding of factors underlying heterogeneity of the DM phenotype. This warrants further studies of genetic factors, including the potential for additional disease genes and genetic modifiers.

Dr. Simone Rost and his colleagues at the University of Würzburg have explored the potential involvement of genetic variants in determination of DM-like phenotypes and recently published their results in the European Journal of Human Genetics. The team started with a cohort of 5,280 patients with a primary clinical diagnosis of DM evaluated in the Würzburg molecular genetics lab over a 10-year period. Of the cohort, 38% had repeat expansions in DMPK or CNBP, while a relatively small portion of the cohort (< 0.5%) was found to have mutations in genes associated with other types of muscular dystrophy (e.g., FSHD1, LMNA, PABPN1). 

A subset of the patients lacking the traditional DM1 and DM2 repeat expansions, but with DM symptomology verified by neurological exam, underwent further genetic analyses. No additional pathologic variants were identified in DMPK, CNBP, or CUGBP; patients were also free of mutations in 27 other muscle disease genes. The study identified three unrelated patients with potentially pathogenic variants in MBNL1.

Mice with mutations in Mbnl1 appear to phenocopy mice containing large DMPK repeat expansions, consistent with the known role of Mbnl1 in the pathogenesis of DM. To evaluate potential splicing changes due to the MBNL1 variants, the Würzburg team performed splicing assays for six genes that are mis-spliced in DM1, using peripheral blood leukocytes from the three patients. The authors failed to identify splicing alterations, but acknowledge the potential tissue specificity of DM mis-splicing.  

Taken together, Dr. Rost and colleagues have linked MBNL1 variants to a DM phenotype. However, despite careful analysis of thousands of patients with DM-like symptoms, only a small number of MBNL1 variants were identified. These findings suggest that MBNL1 mutations may not be more than a minority contributor to DM, and thus other potential gene variants or modifiers should be prioritized for population studies.

Reference:

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype.
Larsen M, Kress W, Schoser B, Hehr U, Müller CR, Rost S.
Eur J Hum Genet. 2016 May 25. doi: 10.1038/ejhg.2016.41.