LINGO1 variants in essential tremor and Parkinson’s disease

Deng, Hao; Gu, Shaojuan; Jankovic, Joseph

doi:10.1111/j.1600-0404.2011.01516.x

Cited by 32 publications

(29 citation statements)

References 64 publications

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“…Given these overlapping features and the association of LINGO 1 with ET, VillarinoGuell et al [14] investigated the role of LINGO1 in PD and their results revealed an association between LINGO1 and risk of PD. Although these results are not confirmed by other reports, further studies of larger populations are required to investigate the role of LINGO1 in PD [18]. From the pathophysiological perspective, traditionally ET is considered as a primary electrical/elctrophysiological entitiy.…”

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confidence: 50%

Recent Advances in Essential Tremor

Goksemin¹

2016

J Mult Scler

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Essential tremor (ET) is the most prevalent tremor disorder. It is characterized by 8-12 Hz action tremor of the arms; head tremor and other cranial tremors may also occur, as well as limb and gait ataxia and subtle eye motion abnormalities [1][2][3][4][5]. The prevalence and incidence increase with age, so that more than 20% of individuals over 90 years have ET [1,6].In recent year's neuroepidemiological, clinical and pathological studies have substantially contributed to the changing of view of ET. The traditional view of ET as a monosymptomatic condition is being replaced by an appreciation of the spectrum of clinical features and clinical associations, with both motor and non-motor features [7][8][9][10][11]. It is even possible that ET might be a family of diseases, unified by the presence of kinetic tremor, but further characterized by etiological, clinical and pathological heterogeneity [10].Both genetic and environmental factors play a role in ET, but the underlying causes are far from fully elaborated. Recent studies have reported a genome-wide significant association between leucinerich repeat and Ig domain containing 1 gene (LINGO1) and risk for essential tremor [12][13][14][15]. Further studies also confirmed this finding in populations of European and Asian descent, showing LINGO1 is likely a risk factor for essential tremor with widespread distribution [14,15]. Parkinson's disease (PD) and ET are regarded as distinct entities, but clinical evidence suggest that there is a considerable overlap. For instance, in some cases action tremor can precede the onset of PD symptoms and there is a fourfold increased risk of developing PD in patients with ET [16]. Moreover, in a number of ET cases Lewy bodies have been identified in the brain stem and imaging studies have found signs of dopaminergic deficits in some patients with ET [17]. Given these overlapping features and the association of LINGO 1 with ET, VillarinoGuell et al. [14] investigated the role of LINGO1 in PD and their results revealed an association between LINGO1 and risk of PD. Although these results are not confirmed by other reports, further studies of larger populations are required to investigate the role of LINGO1 in PD [18]. From the pathophysiological perspective, traditionally ET is considered as a primary electrical/elctrophysiological entitiy. It is the result of pacemaking neurons in the inferior olivary nucleus that fire in a coupled manner, and produce tremor through an abnormal olivocerebellar output. But this olivary model of ET suffers from a number of critical problems, such as lack of evidence that this process is occurring in human ET as well. Another major problem of this model is that there are numerous pacemakers in the central nervous system which are also connected with the cerebellum [19][20][21]. Therefore, olivary pacemakers are not unique. Moreover, the main empiric support of olivary model comes from the harmaline model which is not a model of human disease [22]. Over the past decade an alternative model, cerebella...

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confidence: 50%

Recent Advances in Essential Tremor

Goksemin¹

2016

J Mult Scler

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“…36 Various association studies have also shown the role of LINGO1 variants with essential tremor and Parkinson's disease. 37 Moreover, inhibitory anti-LINGO1 antibodies promoted illegitimate oligodendrocyte differentiation and myelination of neurons by inhibiting the function of LINGO1. A similar outcome was observed in the Lingo1 knockout mice and zebrafish lingo1b knockdown models, which revealed early improvement in neuronal myelination as compared to wild type.…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Ansar

Riazuddin

Sarwar

et al. 2018

Genetics in Medicine

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Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-offunction studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

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“…Surprisingly, genome-wide association studies of LINGO-1 and LINGO2 variations in PD have generally produced negative results, arguing against a role of LINGO1 variations as a contributing factor in the development of PD [for a recent review, see Deng et al ( 2012 )]. However, genome-wide association studies of LINGO1 and -2 variations have revealed an association with essential tremor, a progressive neurological disorder characterized by symmetric postural or kinetic tremor of the hands and forearms [see Deng et al ( 2012 ), Stefansson et al ( 2009 ), Zeuner andDeuschl ( 2012 ) and Vilarino-Guell et al ( 2010 )].…”

Section: Diseasesmentioning

confidence: 99%

“…However, genome-wide association studies of LINGO1 and -2 variations have revealed an association with essential tremor, a progressive neurological disorder characterized by symmetric postural or kinetic tremor of the hands and forearms [see Deng et al ( 2012 ), Stefansson et al ( 2009 ), Zeuner andDeuschl ( 2012 ) and Vilarino-Guell et al ( 2010 )]. …”

Section: Diseasesmentioning

confidence: 99%

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

Winther

Walmod

2013

Advances in Neurobiology

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Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.

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LINGO1 variants in essential tremor and Parkinson’s disease

Cited by 32 publications

References 64 publications

Recent Advances in Essential Tremor

Recent Advances in Essential Tremor

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

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