Dejerine-Sottas

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Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.

May 16, 2010

J Neurol. 2010 May 12
Lee YC, Lin KP, Chang MH, Liao YC, Tsai CP, Liao KK, Soong BW.

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

Abstract
Mutations in MPZ, which encodes myelin protein zero (P(0)), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes.

Nine P(0) mutants associated with CMT1 (P(0)S63F, R98H, R277S, and S233fs), DSS (P(0) I30T and R98C), and CMT2 (P(0)S44F, D75V, and T124M), were investigated. Wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization.

An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes.

Three different intracellular localization patterns of the mutant P(0) were observed. Wild-type P(0), P(0)I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P(0)R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P(0)S233fs formed aggregates within the ER.

Cells expressing mutant P(0), as compared with those expressing wild-type P(0), demonstrated variable degrees of reduction in the cell adhesiveness.

The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors.

This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.

Decoding DNA

March 14, 2010

PBS’ To the Contrary, hosted by Bonnie Erbé, has developed a three-part series called “Decoding DNA: Helping Children With Rare Diseases.” The program looks at genetic mapping and finding cures for children with rare diseases like Charcot-Marie-Tooth Disease. To view the first two parts of the series, please visit PBS at the links below. Part 3 will be shown later this month. Please view your local listing for further information.
Decoding DNA Part 1
Decoding DNA Part 2

Turning Back The Clock For Schwann Cells

May 20, 2008

Myelin-making Schwann cells have an ability every aging Hollywood star would envy: they can become young again. According to a study appearing in the May 19 issue of the Journal of Cell Biology, David B. Parkinson (University College London, London, UK) and collogues have pinned down a protein that returns the cells to their youth, a finding that might help researchers understand why myelin production falters in some diseases.

(more…)

1996 article from New York Times archives explains P0 mutation in Dejerine-Sottas

December 2, 2007

The New York Times recently digitized its pre-Internet archives and opened them to the public, so today I ran a search and found a single mention of Dejerine-Sottas disease. It’s an interesting article on the use of x-ray crystallography to shed some light on the proteins created by the P0 mutation, one of the mutations that causes Dejerine-Sottas.

Protein Linked to 3 Nerve Ailments

IN two papers representing the work of 19 researchers, scientists reported last week that they had seen, at a molecular level, the damage to an important protein that is the cause of three genetic nerve disorders. Dr. Thomas Bird, a professor at the University of Washington and chief of neurology at the Veterans Affairs hospital in Seattle, who is not associated with the groups who made the reports, said that the papers are examples of where medicine has arrived: at the molecular detail of human disease.

Read more of Protein Linked to 3 Nerve Ailments

Probing Myelin Protein Zero Gain of Function Mutants

February 24, 2006

Filed under: Genetics

Lawrence Wrabetz, Maurizio D’Antonio, Maria Pennuto, Gabriele Dati, Elisa Tinelli, Pietro Fratta, Stefano Previtali, Daniele Imperiale, Jurgen Zielasek, Klaus Toyka, Robin L. Avila, Daniel A. Kirschner, Albee Messing, M. Laura Feltri, and Angelo Quattrini
The P0 glycoprotein is the most abundant protein in myelinated nerves. The extracellular immunoglobulin-like fold forms tetramers in trans that allow for the compaction of myelin layers. Although mutations in myelin protein zero [MPZ], P0) are well-known causes of neuropathy, the clinical phenotypes vary widely, in contrast to the mild abnormalities caused by heterozygous loss of function. Thus Wrabetz et al. explored the hypothesis that MPZ-neuropathies are attributable to gain of function mutations. They examined transgenic mice expressing MPZ mutations at S63, either S63del or S63C. S63del is the mutation underlying an adult-onset demyelinating neuropathy (Charcot-Marie-Tooth, Type 1B [CMT1B]), whereas the S63C mutation causes an early-onset demyelinating neuropathy Déjérine-Sottas syndrome). Both mutant alleles caused a demyelinating neuropathy despite the coexistence of normal alleles, consistent with a gain of function mechanism. S63C caused a packing defect in the myelin, whereas S63C was retained in the endoplasmic reticulum and elicited a presumably toxic unfolded protein response. [From Medical News Today.]

New insights into how genetic mutations arise

October 29, 2005

Filed under: Genetics

Researchers at Stanford University have created a larger-than-normal DNA molecule that is copied almost as efficiently as natural DNA.
The findings, reported in the Oct. 25 online edition of the Proceedings of the National Academy of Sciences (PNAS), may reveal new insights into how genetic mutations-tiny mistakes that occur during DNA replication-arise. The discovery was made in the laboratory of Eric Kool, a professor of chemistry at Stanford and co-author of the PNAS study. [Read more]

DNA Machine May Advance Genetic Sequencing for Patients

August 1, 2005

Filed under: Genetics

A new kind of machine for decoding DNA may help bring costs so low that it would be feasible to decode an individual’s DNA for medical reasons. The machine, developed by 454 Life Sciences of Branford, Conn., was used to resequence the genome of a small bacterium in four hours, its scientists report in an article published online today by the journal Nature.
In 1995, when the same bacterium was first sequenced, by Claire M. Fraser, it required 24,000 separate operations spread over four to six months, she said in an e-mail message. [New York Times]

Drawing with DNA: ‘Bioart’ illuminates genomics

July 21, 2005

Filed under: Genetics

Readers in the Los Angeles area may be interested in the following exhibit at SIGGRAPH 2005:

On any given day, tens of thousands of biologists around the globe run DNA sequences of unknown function through a lightning-fast online algorithm called BLAST – typically submitting 200 to 400 base pairs, or “letters” of genetic code, to be matched against the billions of letters for known genes. Searching for similarities that can shed light on functional or evolutionary relationships, scientists routinely use BLAST to churn through and produce vast amounts of data. Everyday applications include genetic medicine and pharmaceuticals. Yet this process and, more generally, genomics remain dimly understood by the public.
Ecce Homology,” an interactive “bioart” installation to be showcased at SIGGRAPH 2005–in Los Angeles, July 31 through Aug. 4–quite literally makes BLAST and genomics visible. [Medical News Today]

Scientists get the lab laugh with amusing gene names

May 16, 2005

Filed under: Genetics

Though not especially informative about the sonic hedgehog gene, this article gives some interesting and amusing insights into the process of naming genes.

Sonic hedgehog makes a protein that sculpts human embryos’ nervous system, limbs and organs. Later in life, it can activate hair growth and contribute to several types of cancer. It’s hugely interesting to stem cell scientists and oncologists.
But the Norwegian scientist who discovered sonic hedgehog 12 years ago now regrets that it’s named after a SEGA video game. He allowed his American collaborators to talk him into adding sonic to the name. The hedgehog part had been decided years before by the irreverent fruit fly scientists.

Clinicopathological and genetic study of early-onset demyelinating neuropathy

October 10, 2004

Filed under: Genetics

Bit of bad news here: researchers studied 20 people with Dejerine-Sottas, CMT4 and other related diseases, and found several new mutations.

Abstract from Brain. 2004 Oct 6
Parman Y, Battaloglu E, Baris I, Bilir B, Poyraz M, Bissar-Tadmouri N, Williams A, Ammar N, Nelis E, Timmerman V, De Jonghe P, Necefov A, Deymeer F, Serdaroglu P, Brophy PJ, Said G.
Department of Neurology, Istanbul University, Istanbul Medical Faculty, Turkey.
Summary: Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene.

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