Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations

Abstract

Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

“…2 A missense substitution in the same codon, but resulting in a change into a different amino acid, c.634T4C (Tyr212Arg), has been reported to be a pathogenetic mutation by others. 13 Frequently, a cysteine residue changes the three-dimensional protein conformation drastically owing to disulfide bond formation with other cysteines. 14 Thus, the amino-acid substitution to cysteine in our patient is likely a pathogenetic mutation, causing PMD.…”

“…1-3 Indeed, Patient 3 showed severely delayed psychomotor development complicated by respiratory and feeding difficulties. His condition can be classified as form 0 according to the classification proposed by Cailloux et al, 13 as form 0 is the most severe form of PMD. Dysmyelination in this patient was particularly severe.…”

“…1 In contrast, patients with PLP1 null mutations escape severe impairments because of the absence of any gain-of-toxic function. 2,13,17 Indeed, knockout mice with a functionally null Plp1 gene do not develop classical signs of Plp1-related disease; their oligodendrocytes develop normally and synthesize compact myelin sheaths. 3,18 However, the mice show ultrastructural abnormalities, including swelling of the small-diameter axons and late-onset axonal degeneration.…”

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

“…Thus, the patient may be classified as form 0 (the most severe), according to the previously described rating scale for clinical classification ranging from 0 to 4 on the basis of the best motor function. 15 The unexpected severe PMLD1 form led to compare the genotype and the phenotype of our patient with existing data from the literature. As shown in Table 1, the majority of PMLD1 patients (46 out of 54) reported in the literature have a score ranging between 3 and 4, with only six and two patients with score 2 and 1, respectively.…”

“…The clinical severity of PMLD1 patients was scored according to the rating scale for clinical classification ranging from 0 to 4 on the basis of the best motor function, used for PMD patients (Table 1). 15 Ethical aspects. Following ethical guidelines, the samples were obtained for analysis and storage with the patient's and/or a family member's written informed consent.…”