Dataset Information

Multifocal demyelinating motor neuropathy associated with a de novo PTEN mutation

ABSTRACT: Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene associated with inherited tumour susceptibility conditions, macrocephaly, autism, ataxia, tremor and epilepsy. Functional implications of this protein have been investigated in Parkinson’s and Alzheimer’s diseases. We describe the first patient presented with multifocal demyelinating motor neuropathy in association with a de novo PTEN mutation. The pathogenicity of the mutation was supported by altered expression of several proteins involved in tumorigenesis and fibroblasts showed a reversible defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4,-trisphosphate, suggesting a novel and potentially treatable mechanism for multi-focal demyelinating motor neuropathy.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Vietxuan Phan

LAB HEAD: Andreas Roos

PROVIDER: PXD008014 | Pride | 2018-10-22

REPOSITORIES: Pride

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Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo <i>PTEN</i> mutation.

Bansagi Boglarka B Phan Vietxuan V Baker Mark R MR O'Sullivan Julia J Jennings Matthew J MJ Whittaker Roger G RG Müller Juliane S JS Duff Jennifer J Griffin Helen H Miller James A L JAL Gorman Grainne S GS Lochmüller Hanns H Chinnery Patrick F PF Roos Andreas A Swan Laura E LE Horvath Rita R

Neurology 20180502 21

<h4>Objective</h4>To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (<i>PTEN</i>), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases.<h4>Methods</h4>We performed whole-exome sequencing in the patient's genomic DNA validate ...[more]

PMID: 29720545

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Project description:Hereditary Motor and Sensory Neuropathies (HMSN) are the most common inherited peripheral neuropathies and comprise a group of genetically heterogeneous diseases. We study the genetic defects causing three demyelinating disorders: HMSN1A, HMSN-LOM and congenital cateracts facial dysmophism neuropathy (CCFDN) syndrome, which are caused by mutations in PMP22, NDRG1 and CTDP1, respectively. The function and patho-mechanisms of these genes is still unknown. To identify effects downstream of the mutations, thereby possibly involved in the disease process, we used Serial expression of gene expression (SAGE) and microarray analysis. We analyzed human Schwann cell lines from three normal subjects, one HMSN-LOM patient, two HMSN-1A patients and two CCFDN patients and compared our data to a recent dataset of human Schwann cells (4 normal subjects passage 1 vs. 3, GDS1869/GSE4030 M.B. Bunge, 2006). We excluded genes that were not consistently regulated between biological and technical replicates and genes that were found to be influenced by passage number (p<0.05). Comparing expression profiles of demyelinating neuropathies with different mutations we identified: 1. expression signatures specific for each genotype. 2. Genes commonly (dys)regulated in all screened neuropathies. Interestingly, these include genes that play a role in reorganization of sodium channels in central and peripheral nerves (S100A10, CD90), or extracellular matrix remodeling (e.g. TGFBI, SERPINE1, THBS1). We also found high up-regulation of genes involved in Schwann cell lineage and in particular, genes that are associated with an immature or pre-myelinating Schwann cell phenotype (i.e. Sox2, Sox10, COL18A1, TFAP2A, Pax3, CDH19). Our study shows that many genes, possibly contributing to nerve pathology can be identified by this approach. Experiment Overall Design: Experimental design: in total 12 (two-color) arrays were run. All neuropathy samples were in duplicate (technical replicates). Two CCFDN and two HMSN1A patients were also analyzed as biological replicates. Three healthy subjects were included from which one was in duplicate. All samples (Cy3) were compared to a common reference pool (Cy5) which consisted of a mix of all samples.

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