Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2

Abstract

Myotonic dystrophy type 2 (DM2) is a common adult onset muscular dystrophy caused by a dominantly transmitted (CCTG)( n ) expansion in intron 1 of the CNBP gene. In DM2 there is no obvious evidence for an intergenerational increase of expansion size, and no congenital cases have been confirmed. We describe the clinical and histopathological features, and provide the genetic and molecular explanation for juvenile onset of myotonia in a 14-year-old female with DM2 and her affected mother presenting with a more severe phenotype despite a later onset of symptoms. Histological and immunohistochemical findings correlated with disease severity or age at onset in both patients. Southern blot on both muscle and blood samples revealed only a small increase in the CCTG repeat number through maternal transmission. Fluorescence in situ hybridization, in combination with MBNL1 immunofluorescence on muscle sections, showed the presence of mutant mRNA and MBNL1 in nuclear foci; the fluorescence intensity and its area appeared to be similar in the two patients. Splicing analysis of the INSR, CLCN1 and MBNL1 genes in muscle tissue demonstrates that the level of aberrant splicing isoforms was lower in the daughter than in the mother. However, in the CLCN1 gene, a heterozygous mutation c.501C>G p.F167L was present in the daughter's DNA and found to be maternally inherited. Biomolecular findings did not explain the unusual young onset in the daughter. The co-segregation of DM2 with a recessive CLCN1 mutation provided the explanation for the unusual clinical findings

Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2

“…While it is clear that MBNL1 is depleted from nucleoplasm through recruitment into ribonuclear inclusions both in DM1 and DM2 even when clinical symptoms and muscle alterations are very mild [35], [62]–[65], CUGBP1 overexpression has been clearly demonstrated in DM1 but not in DM2 muscle biopsies. Our western blotting analysis of CUGBP1 protein expression confirms that CUGBP1 is overexpressed in DM1 muscle biopsies however the increase is evident only in DM1-E2 while CUGBP1 protein levels in DM-E1 and DM1–CDM appear to be similar to those observed in healthy controls.…”

Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes

“…Nevertheless, F167L appears unlikely as a benign polymorphism in ClC-1, because it has never been found in ClC-1 of numerous control individuals. In addition, the contemporaneous occurrence of F167L in a DM2 patient was associated with unusual clinical findings, suggesting a pathogenic role for the ClC-1 channel mutation (Cardani et al, 2012). …”

Report on the 3rd Ottawa International Conference on Neuromuscular Biology, Disease and Therapy – September 24–26, 2015, Ottawa, Canada1

“…MBNL, CUGBP1), and the impact of modifier genes. For example, Dr. Meola described 2 patients with DM2 that had additional heterozygous mutations in CLCN1, which caused an unusually young juvenile-onset myotonia [45]. In an adult patient with DM2, an additional mutation in SCN4A increased the severity of myotonia [46].…”