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The autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD2; OMIM #181350) was the first disorder to be associated with mutations in the LMNA gene, encoding the nuclear envelope proteins lamin A and C.1 Following this, other mutations were reported in limb girdle muscular dystrophy with atrioventricular conduction defects (LGMD1B; OMIM #159001)2 and a conduction system disease with dilated cardiomyopathy (CMD1A; OMIM #115200).3 These disorders are reminiscent of EDMD2, with a predominance of skeletal and cardiac symptoms, respectively, but lacking the early contractures of large joints typical of EDMD. Four more entirely different phenotypes can also be caused by the LMNA gene: (a) partial lipodystrophy (FPLP; OMIM #151660),4 (b) an autosomal recessive variant of Charcot-Marie-Tooth disorder type 2 (CMT2B1; OMIM #605588),5 (c) mandibuloacral dysplasia (MAD; OMIM #248370)6 and (d) Hutchinson-Gilford progeria syndrome (HGPS; OMIM #176670).7 To date, more than 30 mutations have been reported to be associated with the muscular dystrophy phenotype. The majority of these mutations are missense substitutions, but a single case each of a nonsense substitution and a splice site mutation as well as a few small deletions are on record (Leiden Muscular Dystrophy pages, www.dmd.nl). Very recently, reports on mutations that activate cryptic splice sites have been found in the Hutchinson-Gilford progeria syndrome.7,8
Here, we report on a synonymous codon change in the LMNA gene, which leads to abnormal splicing and is likely to cause LGMD1B in a large German pedigree. Such “neutral” synonymous codon changes leading to splicing disorganisation have been described for the hexoseaminidase A,9 calpain 3,10FGFR211 and fibrillin-1 genes.12 Here, we present evidence that the replacement of the last nucleotide in exon 2 of the LMNA gene (c.513G→A) leads to partial skipping of the canonical 5′ splice site in intron …
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