A Missense Mutation in Myelin Oligodendrocyte Glycoprotein as a Cause of Familial Narcolepsy with Cataplexy

Center for Integrative Genomics (CIG), University of Lausanne, Switzerland.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/2011; 89(3):474-9. DOI: 10.1016/j.ajhg.2011.08.007
Source: PubMed


Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

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    • "e cerebral , cerebellar , and brainstem atrophy may also be present ( Melberg et al . , 1999 ; Winkelmann et al . , 2012 ; Moghadam et al . , 2014 ) . DNMT1 mutations in exon 21 have been found to cause ADCA - DN ( Winkelmann et al . , 2012 ) , thus qualifying DNMT1 as the third mutant leading to genetically determined NC ( Peyron et al . , 2000 ; Hor et al . , 2011 ) . A previous link between DNMT1 and NC emerged from a genome - wide study associating NC with the SNP rs4804122 , located in a region of high linkage disequilibrium spanning several genes including DNMT1 , and a weak correlation between this NC - associated allele and lower DNMT1 mRNA expression was also docu - mented in peripheral bl"
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    ABSTRACT: Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5)-methyltransferase 1. DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed?
    Frontiers in Genetics 01/2015; 6. DOI:10.3389/fgene.2015.00090
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    • "He was heterozygous HLA-DQB1*06 : 03/02 : 01. A myelin oligodendrocyte glycoprotein mutation was identified in this family (Hor et al., 2011; see case 5 in Table 1). "
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    ABSTRACT: Evidence suggests that autoimmune diseases tend to co-occur so that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. The association between allergic and autoimmune diseases is also of considerable interest. There are no reports on the association between sporadic or familial narcolepsy with cataplexy and other non-neurological immune-mediated diseases. This study reported on the comorbid immunopathological diseases associated with narcolepsy. One-hundred and fifty six narcoleptic patients with a mean age at diagnosis of 39.1 ± 17.8 years (range, 6–70 years) were assessed using the clinical history, physical and neurological examinations, sleep questionnaires, neuroimaging and human leucocyte antigen typing. Diagnosis was confirmed by polysomnography followed by a multiple sleep latency test or by measuring hypocretin-1 levels. Patients with immunopathological diseases were matched for gender and age at the onset of narcoleptic symptoms with narcoleptic patients without immunopathological diseases. Twenty-six patients (16.6%; 50% women; one familial, 25 sporadic) had one or more immunopathological diseases associated: autoimmune diseases, such as idiopathic thrombocytopenic purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, ulcerative colitis, autoimmune thyroid disease, Peyronie's disease and idiopathic recurrent facial palsy; other immunopathological diseases, like atopic dermatitis, allergic asthma and allergic rhinitis. Although not significant, the age at diagnosis of narcolepsy was 9.3 years earlier in patients with narcolepsy + immunopathological diseases. The results demonstrate that the prevalence of comorbid immunopathological diseases is high in narcolepsy, and cataplexy is significantly more severe in patients with narcolepsy + immunopathological diseases.
    Journal of Sleep Research 03/2014; 23(4). DOI:10.1111/jsr.12143 · 3.35 Impact Factor
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    • "A more recent follow-up showed a polysomnography with marked sleep disruption, a body mass index of 25.1 kg/m 2 , Epworth sleepiness scale score of 15, undetectable cerebrospinal fluid hypocretin-1 levels, IgG index of 1.85 with negative antimyelin oligodendrocyte glycoprotein antibody, and limited positive TRIB2 antibodies and negative plasma antiaquaporin-4 antibodies. Direct sequencing found no mutation in the myelin oligodendrocyte glycoprotein gene, MOG, in our patient [5]. In the literature, none of the recently reported cases of neuromyelitis optica with bilateral hypothalamic lesions and hypocretin deficiency exhibited cataplexy [6], contrary to the seven previously reported sporadic narcoleptic MS cases; however, most of these cases lacked clinical details [7]. "
    Sleep Medicine 05/2013; 14(7). DOI:10.1016/j.sleep.2013.03.015 · 3.15 Impact Factor
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