Pelizaeus-Merzbacher disease: Three novel mutations and implication for locus heterogeneity

Abstract

We report a mutational and polymorphic analysis of the proteolipid protein gene in members of 27 Japanese families with Pelizaeus‐Merzbacher disease. We found causative mutations in 6 members of 27 families (22.2%); 5 of the 6 mutations, including two novel mutations, Leu45Arg and 231 + 2T → G, resulted in the typically severe clinical symptoms. Paradoxically, the Cys219Tyr mutation, presumed to disrupt the tertiary structure of proteolipid protein by removing the disulfide bond between Cys200 and Cys219, was associated with a mild clinical presentation wherein the patient could walk with assistance and speak. It was inferred that the structural change prevented the toxicity associated with a gain of function mutation. Moreover, in one family 3 patients exhibited a intragenic polymorphism that did not segregate with the disease, suggesting a locus heterogeneity for Pelizaeus‐Merzbacher disease. Ann Neurol 1999;45:59–64

Myelin deficiencies in both the central and the peripheral nervous systems associated with aSOX10 mutation

“…20 Mutations in EGR2, in which mutations have recently been described to be associated with peripheral neuropathies, 11,12 were not identified. Duplication and point mutations of PLP, which are associated with the CNS dysmyelinating disorder PMD 17,21 were also excluded.…”

Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations

“…When we use stringent clinical criteria to eliminate some atypical cases, the proportion of PLP duplications would be 85% of the families in which PLP point mutations were excluded. Because only about 20% of PMD cases have PLP point mutations, 18 duplications of the PLP gene are probably the most common genetic abnormality in PMD, possibly accounting for 60 to 70% of all PMD cases. Therefore, screening for PLP duplication by interphase FISH should be considered as an initial molecular diagnostic test.…”

“…Mutations in PLP coding and promoter regions were screened by heteroduplex analysis and sequencing as described elsewhere. 18,24 Of those who did not have PLP mutations, 17 families were available for the col-lection of blood samples to establish lymphoblastoid cell lines. With the addition of 3 new families, a total of 20 families participated in this study.…”

“…Clinical presentations for these duplication cases are summarized and compared with the typical features observed in PMD cases with PLP point mutations (Table 2). 16,18 All cases have the classic form of PMD based on the clinical criteria reported by Seitelberger. 13,14 There was a variation in the severity of clinical features in our families, however; the most mildly affected patient can speak in sentences, walk with assistance, and even calculate three columns of addition, but the most severely affected patient never obtained head control or spoke any words.…”

Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene

“…Missense mutations are identified by single letter amino acid codes, thus the md rat mutation, T74P, specifies the substitution of threonine (wild type) by proline at amino acid 74. example, if we consider the straightforward case of an amino acid that is conserved in all lipophilin genes from all species during evolution from drosophila to mammals-say cysteine 219 -we may speculate about whether a particular amino acid substitution at this position would cause mild disease or severe disease. Would we predict that such a highly conserved amino acid, which is in an extracellular domain and participates in a disulfide bond (Weimbs and Stoffel, 1992), could undergo a non-conservative substitution to tyrosine and yield a mild phenotype (Osaka et al, 1999)? Moreover, what would be the prediction if this amino acid was deleted or if an amino acid was inserted in an adjacent position?…”