Pelizaeus-Merzbacher-like disease: female case report

Nezu, Atsuo; Kimura, Seiji; Uehara, Saori; Osaka, Hitoshi; Kobayashi, Takuya; Haraguchi, Mitsuyo; Inoue, Ken; Kawanishi, Chiaki

doi:10.1016/0387-7604(95)00078-x

Cited by 17 publications

(13 citation statements)

References 17 publications

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“…The recent finding by Osaka and collegues [143], that a mutation in the SOX10 binding site in the GJC2 promoter causes a mild PMLD phenotype [144], intermediate between that of PMLD1 and SPG44, lends support to the idea that in humans, loss of function of Cx47 is pathogenic and that degree of loss of function may predict severity of phenotype. However, these findings do not rule out gain of function as a contributor to the more severe phenotypes.…”

Section: Disease Manifestations Of Gjc2 Mutationsmentioning

confidence: 82%

“…Data from our laboratories [140] suggest that PMLD1 mutations lead to complete loss of gap junctional coupling, while the SPG44 mutation causes radical alterations in gating, predicted to essentially eliminate Cx47-mediated coupling; thus, it is unlikely that the milder phenotype of SPG44 results from retention of a small degree of Cx47 mediated coupling. The recent finding by Osaka and collegues [143], that a mutation in the SOX10 binding site in the GJC2 promoter causes a mild PMLD phenotype [144], intermediate between that of PMLD1 and SPG44, lends support to the idea that in humans, loss of function of Cx47 is pathogenic and that degree of loss of function may predict severity of phenotype. However, these findings do not rule out gain of function as a contributor to the more severe phenotypes.…”

Section: Disease Manifestations Of Gjc2 Mutationsmentioning

confidence: 82%

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Gap junctions in inherited human disorders of the central nervous system

Abrams

Scherer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

101

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CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot-Marie-Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients with CMT1X. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann-Streiff syndrome, a disorder showing substantial overlap with ODDD.

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Section: Disease Manifestations Of Gjc2 Mutationsmentioning

confidence: 82%

Section: Disease Manifestations Of Gjc2 Mutationsmentioning

confidence: 82%

Gap junctions in inherited human disorders of the central nervous system

Abrams

Scherer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

101

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show abstract

“…A subtle perturbation of Cx47 channels fits the minimal phenotype of the patient and thus extends the possible genotype-phenotype correlation that we previously suggested [31] – complete loss-of-function mutations cause PMLD1/HLD2, partial loss-of-function mutations cause SPG44, and the mildly altered function cause a subclinical leukodystrophy. Homozygous promoter mutations in GJC2 result in a phenotype between PMLD1/HLD2 and SPG44 [25, 32]. Promoter mutations may simply reduce expression of Cx47 leading to partial loss of function.…”

Section: Discussionmentioning

confidence: 99%

A new mutation in GJC2 associated with subclinical leukodystrophy

et al. 2014

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Recessive mutations in GJC2, the gene encoding connexin 47 (Cx47), cause Pelizaeus-Merzbacher-like disease type 1 (PMLD1), a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype - Hereditary spastic paraplegia type 44 (SPG44). Here we present evidence that a novel Arg98Leu mutation causes an even milder phenotype - a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady state junctional conductance-junctional voltage (Gj-Vj) relations differed only slightly from those for wild-type Cx47. Our data suggest that that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.

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“…It has been suggested that these cases represent an autosomal recessive form of PMD. [13][14][15][16] In several X-linked recessive disorders X inactivation is skewed in asymptomatic carrier females, so that the X bearing the mutation is preferentially inactivated. 17 This is also found in carriers of cytogenetically detectable deletions and duplications on the X chromosome.…”

Section: Introductionmentioning

confidence: 99%

X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations

Woodward¹,

Kirtland²,

Dlouhy

et al. 2000

Eur J Hum Genet

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Pelizaeus-Merzbacher disease (PMD)is an X-linked recessive disease caused by coding sequence mutations in the PLP gene, sub-microscopic duplications of variable sizes including the PLP gene or very rarely deletions of the PLP gene. We analysed the X inactivation pattern in blood of PMD female carriers with duplications and with point mutations. In the majority of duplication carriers (7/11), the X chromosome bearing the duplication was preferentially inactivated, whereas a random pattern of X inactivation was detected in point mutation carriers (3/3), a deletion carrier (1/1), affected females (4/4) who did not have a recognised mutation and normal control females. However 2/5 non-carrier female relatives of patients with a duplication, had skewed X inactivation. The skewed pattern of inactivation observed in most duplication carriers and not in mutation carriers suggests a) that there is selection against those cells in which the duplicated X chromosome is active and b) other expressed sequences within the duplicated region rather than mutant PLP may be responsible. Since the skewed X inactivation did not segregate with the disease in two families and the pattern of X inactivation was variable among the duplication carriers, the pattern X inactivation is an unsuitable diagnostic tool for female carriers of PMD European Journal of Human Genetics (2000) 8, 449-454.

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Pelizaeus-Merzbacher-like disease: female case report

Cited by 17 publications

References 17 publications

Gap junctions in inherited human disorders of the central nervous system

Gap junctions in inherited human disorders of the central nervous system

A new mutation in GJC2 associated with subclinical leukodystrophy

X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations

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