Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin.

Focally folded myelin has been recognized as a distinctive feature in some individuals with severe inherited demyelinating neuropathy, with an onset in childhood. Such cases have been shown to be genetically heterogeneous. Alterations in the myotubularin-related protein 2 (MTMR2) gene on chromosome 11q22 have recently been shown to give rise to this phenotype. Mutations have been identified in the 3' region of the MTMR2 gene in four unrelated families, in two of whom the disorder had been mapped to chromosome 11q22 by genetic linkage analysis. We have sequenced the entire coding region and flanking intronic regions of the MTMR2 gene in eight families with early onset autosomal recessive neuropathies. Two novel mutations were identified in exon 4 at the 5' end of the MTMR2 gene in an English and an Indian family. The clinical phenotype and sural nerve pathology in these two families differs in severity, with the proband in the English family having an earlier onset and more severe neuropathy with prominent cranial nerve involvement. This is probably due to mutation type and possible involvement of small nucleotide polymorphisms in phenotype modulation. Detailed sural nerve pathology is presented in both cases. Mutations in the MTMR2 gene are thus an important cause of autosomal recessive demyelinating neuropathy. Identifying further mutations and defining their phenotype will help to clarify the genetic classification of this group of disorders.