Rare missense mutations in P2RY11 in narcolepsy with cataplexy

TY - JOUR

T1 - Rare missense mutations in P2RY11 in narcolepsy with cataplexy

AU - Degn, Matilda

AU - Dauvilliers, Yves

AU - Dreisig, Karin

AU - Lopez, Régis

AU - Pfister, Corinne

AU - Pradervand, Sylvain

AU - Rahbek Kornum, Birgitte

AU - Tafti, Mehdi

N1 - © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

PY - 2017/6/1

Y1 - 2017/6/1

N2 - The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy.

AB - The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy.

KW - Adult

KW - Cataplexy/genetics

KW - Exons

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Narcolepsy/genetics

KW - Pedigree

KW - Receptors, Purinergic P2/genetics

KW - Signal Transduction/genetics

U2 - 10.1093/brain/awx093

DO - 10.1093/brain/awx093

M3 - Journal article

C2 - 28460015

SN - 0006-8950

VL - 140

SP - 1657

EP - 1668

JO - Brain

JF - Brain

IS - 6

ER -