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遺伝学教室について

Introduction

遺伝学教室について
JP / EN

国内外で突出する成果

横浜市立大学大学院医学研究科遺伝学は、2003年10月1日より松本直通が開設いたしました。教室の研究の柱を、ヒト遺伝性疾患の遺伝学的原因解明とし、様々な遺伝病の解明に取り組んできました。常に時代の最先端ゲノム解析技術を駆使して、下表にある多くの疾患の原因遺伝子を明らかにしました。

Year Disease Mutated Gene Journal Principal Investigator
2002 Sotos syndrome NSD1 Nat Genet
2004 Marfan syndrome II TGRBR2 Nat Genet
2008 Ohtahara syndrome STXBP1 Nat Genet
2010 West syndrome SPTAN1 AJHG
2010 New Ehlers-Danlos syndrome CHST14 Hum Mut
2011 Microphthalmia syndrome SMOC1 AJHG
2012 Porencephaly COL4A2 AJHG
2013 Schizencephaly COL4A1 Ann Neurol
2011 AR spinocerebellar ataxia SYT14 AJHG
2011 HCAHC POLR3A & POLR3B AJHG
2012 Neonatal metabol decomp UQCRC2 Hum Mut
2012 Coffin-Siris syndrome 5 SWI/SNF genes Nat Genet
2012 Ohtahara syndrome KCNQ2 (allelic) Ann Neurol
2012 Ohtahara syndrome CASK (allelic) Epilepsia
2013 SENDA WDR45 Nat Genet
2013 Nemaline myopathy KLHL40 AJHG
2013 SEMD-JL1 B3GALT6 AJHG
2013 Ohtahara syndrome GNAO1 AJHG
2014 Leigh syndrome GYG2 Hum Genet
2014 Coffin-Siris syndrome SOX11 Nat Commun
2015 Glycosylation disorder COG2 Clin Genet
2015 FCD Type IIb MTOR (somatic) Ann Neurol
2015 Steroid-registant nephrotic syndrome NUP107 AJHG
2015 Spinal extradural arachnoid cyst HOXD4 Plos One
2016 Axial spondylometaphyseal dysplaia C21orf2 Plos One
2016 Hypothalamic Hamartoma OFD1 & GLI3 (somatic) Ann Clin Transl Neurol
2016 Congenital glycosylation disorder PIGG AJHG
2016 MIRAGE syndrome SAMD9 Nat Genet
2016 Progressive neurodegeneration TBCD AJHG
2016 EOEE with optic atrophy AP3P2 AJHG
2017 Nemaline myopathy MYPN AJHG
2017 Pontocerebellar Hypoplasia 7 TOE1 Nat Genet
2017 Weaver syndrome SUZ12 Hum Mut
2017 EOEE CAMK2A/B Ann Clin Transl Neurol
2018 EOEE SETD1B Hum Genet
2018 EOEE CNPY3 AJHG
2018 Infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia OAS1 AJHG
2018 EOEE o r MCA / ID PPP3CA Hum Mol Genet
2018 Neurodegeneration with cerebellar hypoplasia PMPCB AJHG
2018 EOEE CYFIP2 Ann Neurol
2018 EOEE ATP6V1A Brain
2018 Polymicrogyria SCN3A Ann Neurol
2018 Neurodevelopmental disorder FBXO11 AJHG
2018 West syndrome PHACTR1 Brain
2018 Brain small vessel disorder COLGALT1 Ann Neurol
2018 Galloway-Mowat syndrome NUP133 Ann Neurol
2019 Neuronal intranuclear inclusion disease NOTCH2NLC Nat Genet
2019 Neurodevelopmental deficits and epilepsy ACTL6B AJHG
2019 46,XX and 46,XY disorders of sex development MYRF Hum Mol Genet
2019 Skeletal dysplasia of dysosteosclerosis-Pyle disease spectrum and degenerative encephalopathy with brain malformation CSF1R AJHG
2019 Spastic diplegia, ID, cerebral atrophy and corpus callosum hypoplasia MAPK8IP3 Ann Neurol
2019 Syndromic neurodevelopmental disorder SMARCD1 AJHG
2019 Neurodevelopmental disorder POU3F3 AJHG
2019 Liberfarb syndrome PISD Genet Med
2019 Congenital glycosylation disorder PIGB AJHG
2019 Hypothalamic Hamartoma KIAA0556, PTPN11 & DYNC2H1 (somatic) Neurology
2019 Noonan syndrome RRAS2 AJHG
2019 Developmental syndrome with Marfanoid habitus NKAP AJHG
2020 Craniofacial brain abnormality MN1 AJHG
2020 Neuro-ectodermal phenotype RHOA (somatic) Hum Mut
2020 EOEE SEMA6B AJHG
2020 Intelectual disablity with autism, brain malformations, and epilepsy in females DDX3X Neuron
2020 AMeD syndrome ALDH2 and ALDH5 (digenic) Sci Adv
2021 Developmental and epileptic encephalopathy CELF2 Hum Mut
2021 Polymicrogyria ATP1A3 Sci Adv
2021 Neurodevelopmental disorders SATB1 AJHG
2021 LINKED syndrome OTUD5 Sci Adv
2021 Neurodevelopmental delay, intellectual disability and epilepsy NCDN AJHG
2021 Relapsing polychondritis UBA1 (somatic) Ann Rheum Dis
2021 Developmental and epileptic encephalopathy ATP6V0A1 Nat Commun
2021 Sclerosing bone disorder TMEM53 Nat Commun
2021 Neurodevelopmental disorder SHANK1 Genet Med
2021 Sturge-Weber syndrome GNB2 (somatic) Hum Mol Genet
2021 Syndromic intellectual disability GNB2 J Med Genet
2021 Epilepsy MAST3 Ann Neurol
2021 Developmental delay, epilepsy and brain abnormality ARF3 Hum Mol Genet
2021 A new type of osteopetrosis SLC4A2 J Bone Miner Res
2022 Kyphomelic dysplasia KIF5B Clin Genet
2022 CANVAS RFC1 Comp Het Repeats (AAGGG)/(ACAGG) Brain

遺伝子単離の手法

Sotos症候群(Nat Genet 2002)、Marfan症候群2型（Nat Genet 2004）は、孤発例に合併する染色体構造異常の切断点上に位置する断裂した遺伝子から原因を特定しました。大田原症候群（Nat Genet 2008）は孤発例のゲノムマイクロアレー解析で特定した微細欠失内の遺伝子群から特定しました。Coffin-Siris症候群（Nat Genet 2012, Nat Commun 2014）・SENDA (Nat Genet 2013)は次世代シーケンスを使った全エクソーム解析を用いて特定しました。神経核内封入体病（Nat Genet 2019）はロングリードシーケンスを用いて特定したリピート病の一つで、ロングリードシーケンスの全ゲノム解析で、原因を特定した初めてのリピート病です。

当教室は、様々な希少難病の原因解明に関する国家プロジェクトに関わってきました。2010-2013年度網羅的遺伝子解析拠点（厚生労働省難治性疾患克服事業）・2014-2016年度網羅的遺伝子解析拠点（厚生労働省難治性疾患克服事業＞AMED委託費に移行）・2017-2019年オミックス解析拠点（AMED委託費）・2020-2022年全ゲノム解析拠点の拠点班、2015-2017年度・2018-2019年度未診断疾患イニシアチブ（IRUD）の解析センターで、上記のヒト遺伝性疾患の原因解明を行ってきました。

研究の特徴は、最先端ゲノム解析テクノロジーをヒト疾患ゲノム解析に応用していくもので、運用法や方法論が確立していない段階の新規技術を積極的に導入し、解析法を確立と疾患の原因解明を両立して研究を進めて行きます。時に大変な困難が伴いますが、世界の誰よりも早く見たことのない景色を見る（原因を解明する）ために努力しています。

Introduction

The Department of Genetics, Yokohama City University Graduate School of Medicine was established on October 1, 2003 by Dr. Naomichi Matsumoto. The main focus of our research is the elucidation of the genetic causes of various human genetic diseases. Using the most advanced genome analysis technologies of the past, we have identified the causative genes of the various diseases listed in the table below.

Year Disease Mutated Gene Journal Principal Investigator
2002 Sotos syndrome NSD1 Nat Genet
2004 Marfan syndrome II TGRBR2 Nat Genet
2008 Ohtahara syndrome STXBP1 Nat Genet
2010 West syndrome SPTAN1 AJHG
2010 New Ehlers-Danlos syndrome CHST14 Hum Mut
2011 Microphthalmia syndrome SMOC1 AJHG
2012 Porencephaly COL4A2 AJHG
2013 Schizencephaly COL4A1 Ann Neurol
2011 AR spinocerebellar ataxia SYT14 AJHG
2011 HCAHC POLR3A & POLR3B AJHG
2012 Neonatal metabol decomp UQCRC2 Hum Mut
2012 Coffin-Siris syndrome 5 SWI/SNF genes Nat Genet
2012 Ohtahara syndrome KCNQ2 (allelic) Ann Neurol
2012 Ohtahara syndrome CASK (allelic) Epilepsia
2013 SENDA WDR45 Nat Genet
2013 Nemaline myopathy KLHL40 AJHG
2013 SEMD-JL1 B3GALT6 AJHG
2013 Ohtahara syndrome GNAO1 AJHG
2014 Leigh syndrome GYG2 Hum Genet
2014 Coffin-Siris syndrome SOX11 Nat Commun
2015 Glycosylation disorder COG2 Clin Genet
2015 FCD Type IIb MTOR (somatic) Ann Neurol
2015 Steroid-registant nephrotic syndrome NUP107 AJHG
2015 Spinal extradural arachnoid cyst HOXD4 Plos One
2016 Axial spondylometaphyseal dysplaia C21orf2 Plos One
2016 Hypothalamic Hamartoma OFD1 & GLI3 (somatic) Ann Clin Transl Neurol
2016 Congenital glycosylation disorder PIGG AJHG
2016 MIRAGE syndrome SAMD9 Nat Genet
2016 Progressive neurodegeneration TBCD AJHG
2016 EOEE with optic atrophy AP3P2 AJHG
2017 Nemaline mypoathy MYPN AJHG
2017 Pontocerebellar Hypoplasia 7 TOE1 Nat Genet
2017 Weaver syndrome SUZ12 Hum Mut
2017 EOEE CAMK2A/B Ann Clin Transl Neurol
2018 EOEE SETD1B Hum Genet
2018 EOEE CNPY3 AJHG
2018 Infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia OAS1 AJHG
2018 EOEE o r MCA / ID PPP3CA Hum Mol Genet
2018 Neurodegeneration with cerebellar hypoplasia PMPCB AJHG
2018 EOEE CYFIP2 Ann Neurol
2018 EOEE ATP6V1A Brain
2018 Polymicrogyria SCN3A Ann Neurol
2018 Neurodevelopmental disorders FBXO11 AJHG
2018 West syndrome PHACTR1 Brain
2018 Brain small vessel disorder COLGALT1 Ann Neurol
2018 Galloway-Mowat syndrome NUP133 Ann Neurol
2019 Neuronal intranuclear inclusion disease NOTCH2NLC Nat Genet
2019 Neurodevelopmental deficits and epilepsy ACTL6B AJHG
2019 46,XX and 46,XY disorders of sex development MYRF Hum Mol Genet
2019 Skeletal dysplasia of dysosteosclerosis-Pyle disease spectrum and degenerative encephalopathy with brain malformation CSF1R AJHG
2019 Spastic diplegia, ID, cerebral atrophy and corpus callosum hypoplasia MAPK8IP3 Ann Neurol
2019 Syndromic neurodevelopmental disorder SMARCD1 AJHG
2019 Neurodevelopmental disorder POU3F3 AJHG
2019 Liberfarb syndrome PISD Genet Med
2019 Congenital glycosylation disorder PIGB AJHG
2019 Hypothalamic Hamartoma KIAA0556, PTPN11 & DYNC2H1 (somatic) Neurology
2019 Noonan syndrome RRAS2 AJHG
2019 Developmental syndrome with Marfanoid habitus NKAP AJHG
2020 Craniofacial brain abnormality MN1 AJHG
2020 Neuro-ectodermal phenotype RHOA (somatic) Hum Mut
2020 EOEE SEMA6B AJHG
2020 Intelectual disablity with autism, brain malformations, and epilepsy in females DDX3X Neuron
2020 AMeD syndrome ALDH2 and ALDH5 (digenic) Sci Adv
2021 Developmental and epileptic encephalopathy CELF2 Hum Mut
2021 Polymicrogyria ATP1A3 Sci Adv
2021 Neurodevelopmental disorders SATB1 AJHG
2021 LINKED syndrome OTUD5 Sci Adv
2021 Neurodevelopmental delay, intellectual disability and epilepsy NCDN AJHG
2021 Relapsing polychondritis UBA1 (somatic) Ann Rheum Dis
2021 Developmental and epileptic encephalopathy ATP6V0A1 Nat Commun
2021 Sclerosing bone disorder TMEM53 Nat Commun
2021 Neurodevelopmental disorder SHANK1 Genet Med
2021 Sturge-Weber syndrome GNB2 (somatic) Hum Mol Genet
2021 Syndromic intellectual disability GNB2 J Med Genet
2021 Epilepsy MAST3 Ann Neurol
2021 Developmental delay, epilepsy and brain abnormality ARF3 Hum Mol Genet
2021 A new type of osteopetrosis SLC4A2 J Bone Miner Res
2022 Kyphomelic dysplasia KIF5B Clin Genet
2022 CANVAS RFC1 Comp Het Repeats (AAGGG)/(ACAGG) Brain

We have identified the cause of Sotos syndrome (Nat Genet 2002) and Marfan syndrome type 2 (Nat Genet 2004) from broken genes located on the breakpoints of chromosomal structural abnormalities. Coffin-Siris syndrome (Nat Genet 2012, Nat Commun 2014) and SENDA (Nat Genet 2013) were identified from a group of genes within a microdeletion identified by genomic microarray analysis of solitary cases. Coffin-Siris syndrome (Nat Genet 2012, Nat Commun 2014) and SENDA (Nat Genet 2013) were identified using whole exome analysis with next-generation sequencing. Neuronal nuclear inclusion body disease (Nat Genet 2019) is one of the repeat diseases identified using long read sequencing, and is the first repeat disease for which the cause was identified using whole genome analysis of long read sequences.

Our department has been involved in national projects for elucidating the causes of various rare and intractable diseases: 2010-2013 Comprehensive Genetic Analysis Center (Ministry of Health, Labour and Welfare, Project for Overcoming Intractable Diseases), 2014-2016 Comprehensive Genetic Analysis Center (Ministry of Health, Labour and Welfare, Project for Overcoming Intractable Diseases > transferred to AMED contract funding), 2017 -2019 Omics Analysis Center (funded by AMED), 2020-2022 Whole Genome Analysis Center, and 2015-2017 and 2018-2019 Undiagnosed Disease Initiative (IRUD) analysis centers, we have been elucidating the causes of the above human genetic diseases.

Our research is characterized by the application of the state-of-art genome analysis technologies to the analysis of human disease genomes, actively introducing new technologies that have not yet been established in terms of operational methods and methodologies, and conducting research to both establish analysis methods and elucidate the causes of diseases. Although it is sometimes very difficult, we are striving to see the never-before-seen scenery (cause) before anyone else in the world.