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The A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men.

https://arctichealth.org/en/permalink/ahliterature165637
Source
Bone. 2007 Apr;40(4):1006-12
Publication Type
Article
Date
Apr-2007
Author
Anne Saarinen
Ville-Valtteri Välimäki
Matti J Välimäki
Eliisa Löyttyniemi
Kirsi Auro
Piia Uusen
Mairi Kuris
Anna-Elina Lehesjoki
Outi Mäkitie
Author Affiliation
Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Source
Bone. 2007 Apr;40(4):1006-12
Date
Apr-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Alleles
Bone Density - genetics
Calcifediol - blood
Finland
Fractures, Bone - etiology - genetics
Gene Frequency
Humans
LDL-Receptor Related Proteins - genetics
Low Density Lipoprotein Receptor-Related Protein-5
Male
Military Personnel
Osteoporosis - etiology - genetics
Parathyroid Hormone - blood
Polymorphism, Single Nucleotide
Risk factors
Abstract
Polymorphisms in the gene coding for low-density lipoprotein receptor-related protein 5 (LRP5) contribute to variation in bone mass in the general population. Whether this is due to influence on bone mass acquisition or on bone loss thereafter has not been established.
We studied the association of LRP5 polymorphisms with peak bone mass in young men. The study included 235 Finnish men, aged 18.3 to 20.6 years. Lifestyle factors and fracture history were recorded. Bone mineral content (BMC), density (BMD) and scan area were measured for the lumbar spine and proximal femur by dual energy X-ray absorptiometry (DXA). Blood and urine were collected for determination of bone turnover markers, serum 25-OHD and PTH. Genomic DNA was extracted from peripheral blood for genetic analysis of LRP5. Ten single nucleotide polymorphisms in LRP5 were analyzed and correlated with bone parameters.
Only the A1330V polymorphism of LRP5 significantly associated with bone parameters. In comparison with subjects with the AlaAla genotype (n=215), those with AlaVal genotype (n=20) had lower femoral neck BMC (P=0.029) and BMD (P=0.012), trochanter BMC (P=0.0067) and BMD (P=0.015), and total hip BMC (P=0.0044) and BMD (P=0.0089). Fracture history was similar for the genotypes.
The polymorphic valine variant at position 1330 of LRP5 was significantly associated with reduced BMC and BMD values in healthy young Finnish men. The results provide evidence for the crucial role of LRP5 in peak bone mass acquisition.
PubMed ID
17223614 View in PubMed
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BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma.

https://arctichealth.org/en/permalink/ahliterature283323
Source
Ophthalmology. 2016 May;123(5):1112-7
Publication Type
Article
Date
May-2016
Author
Joni A Turunen
Salla Markkinen
Rosi Wilska
Silva Saarinen
Virpi Raivio
Martin Täll
Anna-Elina Lehesjoki
Tero T Kivelä
Source
Ophthalmology. 2016 May;123(5):1112-7
Date
May-2016
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Cohort Studies
Exons - genetics
Female
Finland
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Male
Melanoma - genetics
Middle Aged
Pedigree
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Tumor Suppressor Proteins - genetics
Ubiquitin Thiolesterase - genetics
Uveal Neoplasms - genetics
Young Adult
Abstract
Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish patients with uveal melanoma who live in a high-risk region for this cancer.
Cohort study.
In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives.
Sequencing BAP1.
Pathogenic variants in BAP1.
We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma.
The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.
PubMed ID
26876698 View in PubMed
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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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[Northern epilepsy and the gene error behind it].

https://arctichealth.org/en/permalink/ahliterature188468
Source
Duodecim. 2002;118(15):1551-8
Publication Type
Article
Date
2002
Author
Susanna Ranta
Aune Hirvasniemi
Riitta Herva
Matti Haltia
Anna-Elina Lehesjoki
Author Affiliation
Folkhälsanin perinnöllisyystieteen laitos, Haartman-instituutti, lääketieteellisen genetiikan osasto Biomedicum Helsinki PL 63, 00014 Helsingin yliopisto sekä Jorvin sairaala 02740 Espoo. susanna.ranta@helsinki.fi
Source
Duodecim. 2002;118(15):1551-8
Date
2002
Language
Finnish
Publication Type
Article
Keywords
Animals
Epilepsy - diagnosis - epidemiology - genetics
Finland - epidemiology
Humans
Intellectual Disability - diagnosis - epidemiology - genetics
Membrane Proteins - genetics
Mice
Neuronal Ceroid-Lipofuscinoses - diagnosis - epidemiology - genetics
Pedigree
Point Mutation
Prognosis
Syndrome
PubMed ID
12244629 View in PubMed
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Refining the phenotype of Unverricht-Lundborg disease (EPM1): a population-wide Finnish study.

https://arctichealth.org/en/permalink/ahliterature263754
Source
Neurology. 2015 Apr 14;84(15):1529-36
Publication Type
Article
Date
Apr-14-2015
Author
Jelena Hyppönen
Marja Äikiä
Tarja Joensuu
Petro Julkunen
Nils Danner
Päivi Koskenkorva
Ritva Vanninen
Anna-Elina Lehesjoki
Esa Mervaala
Reetta Kälviäinen
Source
Neurology. 2015 Apr 14;84(15):1529-36
Date
Apr-14-2015
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Age of Onset
Child
Cystatin B - genetics
Female
Finland - epidemiology
Humans
Male
Middle Aged
Motor Cortex - physiopathology
Mutation
Myoclonus - physiopathology
Phenotype
Severity of Illness Index
Time Factors
Transcranial Magnetic Stimulation
Unverricht-Lundborg Syndrome - epidemiology - genetics - physiopathology
Young Adult
Abstract
This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene.
The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex.
An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP.
As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.
PubMed ID
25770194 View in PubMed
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