Rare Neurodegenerative Diseases

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.