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Kleine-Levin syndrome is associated with LMOD3 variants

Al Shareef, SM; Basit, S; Li, S; Pfister, C; Pradervand, S; Lecendreux, M; Mayer, G; ... Tafti, M; + view all (2019) Kleine-Levin syndrome is associated with LMOD3 variants. Journal Of Sleep Research , 28 (3) , Article e12718. 10.1111/jsr.12718. Green open access

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Abstract

Kleine‐Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first‐degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking. Here we performed whole genome single‐nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage interval. The variant was found to segregate in all affected and one presumably unaffected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other low frequency or rare missense variants in seven cases that were inherited with incomplete penetrance. LMOD3 is expressed in the brain and colocalized with major structures involved in the regulation of vigilance states. LMOD proteins are structural proteins and seem to be developmentally regulated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease.

Type: Article
Title: Kleine-Levin syndrome is associated with LMOD3 variants
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jsr.12718
Publisher version: https://doi.org/10.1111/jsr.12718
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Periodic hypersomnia, Leiomodin 3, lateral hypothalamus, hypocretin, exome, linkage.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10087796
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