Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease

Hurst, Stephanie; Garbern, James; Trepanier, Angela; Gow, Alexander

doi:10.1097/01.gim.0000223551.95862.c3

Cited by 36 publications

(33 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A female patient (Patient P9), carrying a novel nonsense mutation, presented with progressive spastic paraplegia and gait ataxia, followed by executive dysfunction and impaired visual memory. It has been shown that symptoms manifest more commonly in female patients carrying nonsense mutations in PLP1 (Hurst et al , 2006). A male patient (Patient P10), carrying a novel frameshift mutation, presented with a ‘no-no’ head tremor, gait disturbance and bowel and bladder symptoms at age 30 years.…”

Section: Resultsmentioning

confidence: 99%

Clinical and genetic characterization of leukoencephalopathies in adults

Lynch¹,

Paiva

Zhang³

et al. 2017

Brain

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Clinical and genetic characterization of leukoencephalopathies in adults

Lynch¹,

Paiva

Zhang³

et al. 2017

Brain

View full text Add to dashboard Cite

show abstract

“…An alternative explanation is probably more common in most other families. Several investigators have observed an inverse correlation within PMD families: in families with severely affected males, the heterozygous women are unlikely to have clinical manifestations of PMD/ SPG2, whereas in families with mildly affected males, heterozygous females are more likely to have symptoms [156][157][158]. In a family with a particularly mild syndrome characterized by ataxia and mild spastic paraplegia, all three heterozygous females had neurological signs [65].…”

Section: Neurobiological Effects In Heterozygotesmentioning

confidence: 91%

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Garbern

2006

Cell. Mol. Life Sci.

166

147

View full text Add to dashboard Cite

Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system. The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing future disease-specific therapies.

show abstract

“…In the more severe ''connatal'' form, symptoms arise early in infancy and are typically fatal within the first few years of life. Lastly, a few males and most of the exceedingly rare females who present with PMD can develop mild, late-onset spasticity in the legs or assorted mild peripheral neuropathies with minimal CNS deficits 32 (also see GeneReviews in Web Resources). This significant clinical heterogeneity has been attributed to hundreds of different mutations of PLP1.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

show abstract

Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease

Cited by 36 publications

References 43 publications

Clinical and genetic characterization of leukoencephalopathies in adults

Clinical and genetic characterization of leukoencephalopathies in adults

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Contact Info

Product

Resources

About