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Rare Neurodegenerative Diseases

European Society of Human Genetics. Glasgow, 6-9 June 2015

Carmen Espinós and Eduardo Calpena have attended to the conference of the European Society of Human Genetics held in Glasgow in June 6th-9th. They presented a written communication related to the research about Neurodegeneration Brain Iron Accumulation (NBIA) disorders and an oral presentation about the role of junctophilin-1 as genetic modifier of the GDAP1 gene. Eduardo Calpena was chosen as candidate for young investigator awards. 


They study the characterization of a new gene involved in hereditary neuropathy clinical form of recurrent

Dr. Carmen Espinós, Miguel Servet CIBERER researcher at the Centro de Investigación Príncipe Felipe, is leading an investigation that has identified a likely pathological change in a gene involved in new clinical form of recurrent hereditary neuropathy. The work was presented at the XXVII Congress of the Spanish Society of Human Genetics (AEGH) by Eduardo Calpena predoctoral student, who was awarded a scholarship awarded to the best oral communications presented.


JPH 1 gene characterized as the modifier CMT clinical expression caused by mutations in the gene GDAP1

U732 CIBERER researchers have led an investigation discloses that JPH1 gene (juntofilina-1) acts as a modulator of the clinical expression of neuropathy Charcot-Marie-Tooth (CMT) caused by mutations in the GDAP1 gene. JPH1 is a good positional and functional candidate as a genetic modifier. JPH1-GDAP1 the cluster genes are conserved in vertebrates and additionally proteins encoded by the two genes are related to mitochondrial dynamics and involved in calcium homeostasis. The authors have shown that JPH1 is able to restore the SOCE activity (store-operated calcium entry) in cells silenced for GDAP1.

Among the different clinical forms of CMT neuropathy due to mutations in the GDAP1 gene, shape autosomal dominant CMT type 2K (CMT2K) presents with a wide clinical variability. In a mutational screening JPH1 gene in a series of 24 patients with CMT2K GDAP1 mutation carriers p.R120W, they identified a patient with JPH1 change p.R213P having a more severe clinical picture. In cells silenced for GDAP1 when JPH1 p.R213P carries the mutation is not able to recover the SOCE activity and combination of both mutations SOCE greatly reduces activity. This work has led to the conclusion that JPH1 and GDAP1 share a common path in which JPH1 act as a negative modifier p.R120W GDAP1 mutation and thus aggravate the clinic that these patients manifest.

This collaborative research published in Human Molecular Genetics has been led by Dr. Francesc Palau and Dr. Carmen Espinós, U732 CIBERER researchers at the Research Centre Prince Felipe de Valencia. Han researchers Hospital La Fe participated belonging to the CIBERER U763, and the Hospital Universitario Virgen del Rocío de Sevilla. The work is part of the TREAT-CMT Project funded by the Instituto de Salud Carlos III and promoted by the international consortium IRDiRC.


Explanation image

(A) Family tree of family carrier p.R120W GDAP1 mutation, which has been identified variant p.R213P JPH1 and acts as a negative modifier. (B) Confocal fluorescence image showing colocalization between JPH1 (green) and activator STIM1 SOCE (red) in SH-SY5Y cells. In blue you can see the mitochondria. Presence of "onion bulbs" without axon (C) and mitochondrial abnormalities (D) in sural nerve biopsies of patients studied family.


TREAT-CMT researchers describe the relationship between the NRG1 / ErbB route myelination and neuropathy Charcot-Marie-Tooth (CMT)

Doctors Carmen Espinós and Francesc Palau, the U732 CIBERER and Prince Felipe Research Center, participated in research published in GLIA on the relationship between the NRG1 / ErbB and route CMT conducted jointly with the group led by Dr. Roman Chrast at the University of Lausanne. This work is the result mainly of stay of Dr. Vincenzo Lupo, CIBERER researcher in the laboratory of Dr. Chrast.

Mutations in the gene cause SH3TC2 CMT demyelinating neuropathy 4C autosomal recessive (CMT4C). SH3TC2 is specifically expressed in Schwann cells and is necessary for proper myelination of peripheral axons. In line with earlier onset of neuropathy observed in patients with CMT4C, studies of the mouse model of CMT4C made in this investigation have shown that the properties of myelinating Schwann cells deficient in SH3TC2 are affected at an early stage. This phenotype is associated with early changes in the canonical pathway NRG1 / ErbB involved in controlling myelination.

Responsible for the research have shown that ErbB2 SH3TC2 interacts with and plays a role in the regulation of intracellular trafficking ErbB2 from the plasma membrane upon activation by NRG1. SH3TC2 both function loss in mice as pathological mutations present in patients CMT4C affect internalization of ErbB2, potentially altering the subsequent intracellular signaling pathways. Overall, the results indicate that the molecular mechanism for detecting the size axon is disturbed in myelinating Schwann cells deficient in SH3TC2-deficient, thus providing a new understanding of the pathophysiology of the neuropathy CMT4C.

GLIA article