MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

Satake, Tomoko; Yamashita, Kazunari; Hayashi, Kenji; Miyatake, Satoko; Tamura‐Nakano, Miwa; Doi, Hiroshi; Furuta, Yasuhide; Shioi, Go; Miura, Eriko; Takeo, Yukari H.; Yoshida, Katsumi; Yahikozawa, Hiroyuki; Matsumoto, Naomichi; Yuzaki, Michisuke; Suzuki, Atsushi

doi:10.15252/embj.201695630

Cited by 44 publications

(56 citation statements)

References 54 publications

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“…WES, together with family studies, showed the disease in proband 5 could potentially be caused by biallelic MTCL1 gene variants (MIM: 615766, online supplementary table 2) . MTCL1 is involved in axon formation,47 however it has not been linked to human disease and the detected variants are predicted to be benign. Considering this, we speculate that the disease in proband 5 could be caused by LRPE.…”

Section: Discussionmentioning

confidence: 99%

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points toEFNA5,BAHD1andPPP2R5Eas novel candidates for genes causing human Mendelian disorders

et al. 2018

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BackgroundMapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients.MethodsShallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts.ResultsIn all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter.ConclusionSGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene–disease associations.

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Section: Discussionmentioning

confidence: 99%

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points toEFNA5,BAHD1andPPP2R5Eas novel candidates for genes causing human Mendelian disorders

et al. 2018

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“…The disruption of SOGA2 could lead to abnormal motor coordination with Purkinje cell degeneration. It is suggested that dysfunction of SOGA2 might be associated with the pathogenesis of spinocerebellar ataxia …”

Section: Discussionmentioning

confidence: 99%

“…It is suggested that dysfunction of SOGA2 might be associated with the pathogenesis of spinocerebellar ataxia. 29 For a subset of genes, duplication or deletion could result in altered gene dosage, which could lead to a series of phenotypic effects.…”

Section: Discussionmentioning

confidence: 99%

Prenatal detection of interstitial 18p11.31‐p11.22 microduplications: Phenotypic diversity and literature review

Zhang

Yue

et al. 2019

Prenatal Diagnosis

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Introduction Pure duplication of chromosome 18p is rare, with clinical phenotypes ranging from normal or slight abnormalities to various degrees of mental retardation. It remains difficult to establish a clear genotype‐phenotype correlation. Methods Chromosomal karyotyping analysis was performed on cultured amniotic fluid cells from three cases. Single nucleotide polymorphism (SNP) array analysis was carried out using the Illumina Human CytoSNP‐12 BeadChip. We also carried out a review of the literature regarding 18p11 microduplication. Results G‐banding analysis showed that the three cases had normal karyotypes. SNP array results showed 0.48‐ to 1.6‐Mb microduplications of 18p11.31‐p11.22 (chr18: 6995739‐8713088) in these cases, encompassing different degrees of LAMA1 duplication. Follow‐up analysis showed that the parents of both cases 1 and 2 chose termination of pregnancy. Case 3 presented with normal growth and physical development. Currently, there is not enough evidence supporting the pathogenicity of LAMA1 triplosensitivity. Conclusion We described three prenatal cases with 18p11.31‐p11.22 microduplications involving part of the LAMA1 locus. There might be phenotypic diversity associated with 18p11.31‐p11.22 microduplications. To avoid unnecessary abortions for pregnancies such as these, comprehensive genetic counseling should be offered.

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“…We found a novel homozygous loss of function variant in the microtubule cross-linking factor 1 (MTCL1) gene that has recently been reported to be essential for the maintenance of Purkinje neurons in mouse models. 3 We propose that MTCL1 is a novel candidate gene for ARCA.…”

Section: Introductionmentioning

confidence: 99%

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene

et al. 2019

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Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort.

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MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

Cited by 44 publications

References 54 publications

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points toEFNA5,BAHD1andPPP2R5Eas novel candidates for genes causing human Mendelian disorders

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points toEFNA5,BAHD1andPPP2R5Eas novel candidates for genes causing human Mendelian disorders

Prenatal detection of interstitial 18p11.31‐p11.22 microduplications: Phenotypic diversity and literature review

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene

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