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Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.

https://arctichealth.org/en/permalink/ahliterature282304
Source
Am J Hum Genet. 2016 Sep 01;99(3):683-94
Publication Type
Article
Date
Sep-01-2016
Author
Mikko Muona
Ryosuke Ishimura
Anni Laari
Yoshinobu Ichimura
Tarja Linnankivi
Riikka Keski-Filppula
Riitta Herva
Heikki Rantala
Anders Paetau
Minna Pöyhönen
Miki Obata
Takefumi Uemura
Thomas Karhu
Norihisa Bizen
Hirohide Takebayashi
Shane McKee
Michael J Parker
Nadia Akawi
Jeremy McRae
Matthew E Hurles
Outi Kuismin
Mitja I Kurki
Anna-Kaisa Anttonen
Keiji Tanaka
Aarno Palotie
Satoshi Waguri
Anna-Elina Lehesjoki
Masaaki Komatsu
Source
Am J Hum Genet. 2016 Sep 01;99(3):683-94
Date
Sep-01-2016
Language
English
Publication Type
Article
Keywords
Alleles
Animals
Animals, Newborn
Apoptosis
Brain Diseases - genetics - metabolism - pathology
Central Nervous System - metabolism - pathology
Cohort Studies
Epilepsy - genetics
Exome - genetics
Exons - genetics
Fibroblasts - metabolism - pathology
Finland
Gene Frequency
Heterozygote
Humans
Infant
Intellectual Disability - genetics
Mice
Mice, Knockout
Microcephaly - genetics - pathology
Mutation - genetics
Neurons - metabolism - pathology
Proteins - genetics - metabolism
Spasms, Infantile - genetics - metabolism
Ubiquitin - metabolism
Ubiquitin-Activating Enzymes - genetics
Abstract
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.
Notes
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PubMed ID
27545674 View in PubMed
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Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland.

https://arctichealth.org/en/permalink/ahliterature298339
Source
Nat Commun. 2019 01 24; 10(1):410
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
01-24-2019
Author
Mitja I Kurki
Elmo Saarentaus
Olli Pietiläinen
Padhraig Gormley
Dennis Lal
Sini Kerminen
Minna Torniainen-Holm
Eija Hämäläinen
Elisa Rahikkala
Riikka Keski-Filppula
Merja Rauhala
Satu Korpi-Heikkilä
Jonna Komulainen-Ebrahim
Heli Helander
Päivi Vieira
Minna Männikkö
Markku Peltonen
Aki S Havulinna
Veikko Salomaa
Matti Pirinen
Jaana Suvisaari
Jukka S Moilanen
Jarmo Körkkö
Outi Kuismin
Mark J Daly
Aarno Palotie
Author Affiliation
Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
Source
Nat Commun. 2019 01 24; 10(1):410
Date
01-24-2019
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
CRADD Signaling Adaptor Protein - genetics
Cognitive Dysfunction - epidemiology - genetics
Cohort Studies
DNA Copy Number Variations - genetics
Exome
Female
Finland - epidemiology
Genetic Association Studies
Genetic Diseases, Inborn - epidemiology - genetics
Genetic Predisposition to Disease
Genetic Variation - genetics
Genome, Human - genetics
Geography
Homozygote
Humans
Intellectual Disability - diagnosis - epidemiology - genetics
Male
Multifactorial Inheritance
Mutation
Neurodevelopmental Disorders - epidemiology - genetics
Pathology, Molecular
Prevalence
Whole Exome Sequencing
Abstract
The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.
PubMed ID
30679432 View in PubMed
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Identification as a Mutation Carrier and Effects on Life According to Experiences of Finnish Male BRCA1/2 Mutation Carriers.

https://arctichealth.org/en/permalink/ahliterature303047
Source
J Genet Couns. 2018 08; 27(4):874-884
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
08-2018
Author
Outi Kajula
Outi Kuismin
Helvi Kyngäs
Author Affiliation
Research Unit of Nursing Science and Health Management, Faculty of Medicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland. outi.kajula@oulu.fi.
Source
J Genet Couns. 2018 08; 27(4):874-884
Date
08-2018
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adult
BRCA2 Protein - genetics
Breast Neoplasms, Male - genetics - prevention & control
Finland
Genetic Counseling - psychology
Genetic Testing - methods
Humans
Life Style
Male
Men's health
Middle Aged
Mutation
Abstract
Earlier studies have explored post-identification experiences of male BRCA1/2 mutation carriers, but more detailed knowledge of both their experiences and effects of identification as a carrier on their lives is required to improve genetic counseling. Thus, the aim of this study was to acquire deeper and broader insights into their experiences. Qualitative data were collected from theme-based interviews with 31 men carrying BRCA1/2 mutations in Finland, and analyzed using inductive content analysis. Three categories of the participants' responses to identification as BRCA1/2 mutation carriers were identified (personal, offspring-related and related to other relatives), mainly concerning issues associated with cancer, hereditary transmission of their mutations, and life decisions. Although there were many neutral responses regarding the issues, there were also strong emotional reactions and cancer worries. Identification as a carrier also had several effects on participants' lifestyles, including adoption of healthier and disease-preventing behavior, and social well-being, such as family planning and attitudes to life. The results provide detailed information about several aspects of male BRCA1/2 mutation carriers' experiences, which could be used to develop a tentative model of tailored genetic counseling for them.
PubMed ID
29332197 View in PubMed
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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

https://arctichealth.org/en/permalink/ahliterature299077
Source
Nat Commun. 2019 03 19; 10(1):1252
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
03-19-2019
Author
Eevi Kaasinen
Outi Kuismin
Kristiina Rajamäki
Heikki Ristolainen
Mervi Aavikko
Johanna Kondelin
Silva Saarinen
Davide G Berta
Riku Katainen
Elina A M Hirvonen
Auli Karhu
Aurora Taira
Tomas Tanskanen
Amjad Alkodsi
Minna Taipale
Ekaterina Morgunova
Kaarle Franssila
Rainer Lehtonen
Markus Mäkinen
Kristiina Aittomäki
Aarno Palotie
Mitja I Kurki
Olli Pietiläinen
Morgane Hilpert
Elmo Saarentaus
Jaakko Niinimäki
Juhani Junttila
Kari Kaikkonen
Pia Vahteristo
Radek C Skoda
Mikko R J Seppänen
Kari K Eklund
Jussi Taipale
Outi Kilpivaara
Lauri A Aaltonen
Author Affiliation
Department of Medical and Clinical Genetics, University of Helsinki, FI-00014, Helsinki, Finland.
Source
Nat Commun. 2019 03 19; 10(1):1252
Date
03-19-2019
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adult
Atherosclerosis - genetics - pathology
Cells, Cultured
DNA (Cytosine-5-)-Methyltransferases - genetics - metabolism
DNA Methylation - genetics
DNA-Binding Proteins - genetics - metabolism
Epigenesis, Genetic
Female
Finland
Genetic Predisposition to Disease
Germ-Line Mutation
Haploinsufficiency
Hematopoiesis - genetics
Hodgkin Disease - blood - genetics - pathology
Humans
Male
Phenotype
Primary Cell Culture
Proto-Oncogene Proteins - genetics - metabolism
RNA, Small Interfering - metabolism
Whole Genome Sequencing
Abstract
Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
PubMed ID
30890702 View in PubMed
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Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

https://arctichealth.org/en/permalink/ahliterature275360
Source
Nat Neurosci. 2016 Apr;19(4):571-7
Publication Type
Article
Date
Apr-2016
Author
Tarjinder Singh
Mitja I Kurki
David Curtis
Shaun M Purcell
Lucy Crooks
Jeremy McRae
Jaana Suvisaari
Himanshu Chheda
Douglas Blackwood
Gerome Breen
Olli Pietiläinen
Sebastian S Gerety
Muhammad Ayub
Moira Blyth
Trevor Cole
David Collier
Eve L Coomber
Nick Craddock
Mark J Daly
John Danesh
Marta DiForti
Alison Foster
Nelson B Freimer
Daniel Geschwind
Mandy Johnstone
Shelagh Joss
Georg Kirov
Jarmo Körkkö
Outi Kuismin
Peter Holmans
Christina M Hultman
Conrad Iyegbe
Jouko Lönnqvist
Minna Männikkö
Steve A McCarroll
Peter McGuffin
Andrew M McIntosh
Andrew McQuillin
Jukka S Moilanen
Carmel Moore
Robin M Murray
Ruth Newbury-Ecob
Willem Ouwehand
Tiina Paunio
Elena Prigmore
Elliott Rees
David Roberts
Jennifer Sambrook
Pamela Sklar
David St Clair
Juha Veijola
James T R Walters
Hywel Williams
Patrick F Sullivan
Matthew E Hurles
Michael C O'Donovan
Aarno Palotie
Michael J Owen
Jeffrey C Barrett
Source
Nat Neurosci. 2016 Apr;19(4):571-7
Date
Apr-2016
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Cohort Studies
Female
Finland - epidemiology
Genetic Association Studies - methods
Genetic Predisposition to Disease - epidemiology - genetics
Genetic Variation - genetics
Histone-Lysine N-Methyltransferase - genetics
Humans
Male
Neurodevelopmental Disorders - diagnosis - epidemiology - genetics
Schizophrenia - diagnosis - epidemiology - genetics
Abstract
By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
Notes
Comment In: Nat Neurosci. 2016 Apr;19(4):525-727021940
PubMed ID
26974950 View in PubMed
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