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1.
J Inherit Metab Dis ; 42(5): 909-917, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31059585

RESUMO

Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of "off-target reads" deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues).

2.
Neurobiol Aging ; 49: 217.e1-217.e4, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27814993

RESUMO

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.


Assuntos
Epistasia Genética/genética , Estudos de Associação Genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Estudos Multicêntricos como Assunto , Doença de Parkinson/genética , Humanos , Risco
3.
Am J Hum Genet ; 98(2): 358-62, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26805782

RESUMO

Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial ß-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.


Assuntos
Alelos , Arritmias Cardíacas/genética , Cardiomiopatias/genética , Mutação , Arritmias Cardíacas/diagnóstico , Cardiomiopatias/diagnóstico , Pré-Escolar , Exoma , Feminino , Humanos , Lactente , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Linhagem
4.
Acta Derm Venereol ; 96(4): 468-72, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26608363

RESUMO

Punctate palmoplantar keratoderma (PPKP1; Buschke-Fischer-Brauer) is a rare autosomal dominant inherited skin disease characterized by multiple hyperkeratotic papules involving the palms and soles. Mutations have been found at 2 loci, on chromosomes 15q22-15q24 and 8q24.13-8q24.21. We recently identified mutations in 3 families, in the AAGAB gene on 15q, which encodes the alpha- and gamma-adaptin-binding protein p34. The current study examined 14 additional families, comprising a total of 26 affected individuals and identified 8 novel mutations in 9 families. In one family a mutation that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found (1, 2). These results confirm the role of AAGAB in PPKP1. Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype-phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fatores de Risco , Adulto Jovem
5.
Neurology ; 85(15): 1283-92, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26354989

RESUMO

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.


Assuntos
Frequência do Gene/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Peptídeos/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Ataxinas/genética , Ataxinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Doença de Parkinson/epidemiologia , Fenótipo , Risco
6.
PLoS One ; 10(4): e0123082, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25848766

RESUMO

Osteosarcoma (OS), a bone tumor, exhibit a complex karyotype. On the genomic level a highly variable degree of alterations in nearly all chromosomal regions and between individual tumors is observable. This hampers the identification of common drivers in OS biology. To identify the common molecular mechanisms involved in the maintenance of OS, we follow the hypothesis that all the copy number-associated differences between the patients are intercepted on the level of the functional modules. The implementation is based on a network approach utilizing copy number associated genes in OS, paired expression data and protein interaction data. The resulting functional modules of tightly connected genes were interpreted regarding their biological functions in OS and their potential prognostic significance. We identified an osteosarcoma network assembling well-known and lesser-known candidates. The derived network shows a significant connectivity and modularity suggesting that the genes affected by the heterogeneous genetic alterations share the same biological context. The network modules participate in several critical aspects of cancer biology like DNA damage response, cell growth, and cell motility which is in line with the hypothesis of specifically deregulated but functional modules in cancer. Further, we could deduce genes with possible prognostic significance in OS for further investigation (e.g. EZR, CDKN2A, MAP3K5). Several of those module genes were located on chromosome 6q. The given systems biological approach provides evidence that heterogeneity on the genomic and expression level is ordered by the biological system on the level of the functional modules. Different genomic aberrations are pointing to the same cellular network vicinity to form vital, but already neoplastically altered, functional modules maintaining OS. This observation, exemplarily now shown for OS, has been under discussion already for a longer time, but often in a hypothetical manner, and can here be exemplified for OS.


Assuntos
Neoplasias Ósseas/genética , Osteossarcoma/genética , Adolescente , Adulto , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genes Neoplásicos , Estudos de Associação Genética , Heterogeneidade Genética , Genoma Humano , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Osteossarcoma/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , Adulto Jovem
7.
Am J Hum Genet ; 96(5): 826-31, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25913036

RESUMO

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Réunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities.


Assuntos
Metionina tRNA Ligase/genética , Proteinose Alveolar Pulmonar/genética , Adolescente , Alelos , Criança , Pré-Escolar , Retículo Endoplasmático/genética , Retículo Endoplasmático/patologia , Feminino , Complexo de Golgi/genética , Complexo de Golgi/patologia , Humanos , Masculino , Mutação de Sentido Incorreto , Biossíntese de Proteínas , Proteinose Alveolar Pulmonar/patologia , Adulto Jovem
8.
Eur J Hum Genet ; 23(10): 1328-33, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25604855

RESUMO

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (ß-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aß mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aß spectrum from Aß40 to Aß39 and Aß37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Variação Genética/genética , Doença de Parkinson/genética , Idoso , Doença de Alzheimer/genética , Linhagem Celular , Proteínas de Ligação a DNA/genética , Demência/genética , Feminino , Frequência do Gene/genética , Genótipo , Células HEK293 , Humanos , Masculino , Doenças Neurodegenerativas/genética
9.
PLoS One ; 9(4): e93844, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24740359

RESUMO

BACKGROUND: We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility. MATERIALS AND METHODS: We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842) using linear regression models and Bonferroni correction. RESULTS: In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit) and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs) were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene™ vs. Tempus™ tubes) did not affect reproducibility (separate overall replication overlap: 78% and 82%). Immune response pathways were enriched in cis- and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%). Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis. CONCLUSIONS: Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.


Assuntos
Sangue/metabolismo , Regulação da Expressão Gênica , Mapeamento Cromossômico , Redes Reguladoras de Genes , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Modelos Lineares , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
10.
Eur J Hum Genet ; 21(1): 48-54, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22692066

RESUMO

Genome-wide association studies (GWASs) have uncovered susceptibility loci for a large number of complex traits. Functional interpretation of candidate genes identified by GWAS and confident assignment of the causal variant still remains a major challenge. Expression quantitative trait (eQTL) mapping has facilitated identification of risk loci for quantitative traits and might allow prioritization of GWAS candidate genes. One major challenge of eQTL studies is the need for larger sample numbers and replication. The aim of this study was to evaluate the robustness and reproducibility of whole-blood eQTLs in humans and test their value in the identification of putative functional variants involved in the etiology of complex traits. In the current study, we performed comphrehensive eQTL mapping from whole blood. The discovery sample included 322 Caucasians from a general population sample (KORA F3). We identified 363 cis and 8 trans eQTLs after stringent Bonferroni correction for multiple testing. Of these, 98.6% and 50% of cis and trans eQTLs, respectively, could be replicated in two independent populations (KORA F4 (n=740) and SHIP-TREND (n=653)). Furthermore, we identified evidence of regulatory variation for SNPs previously reported to be associated with disease loci (n=59) or quantitative trait loci (n=20), indicating a possible functional mechanism for these eSNPs. Our data demonstrate that eQTLs in whole blood are highly robust and reproducible across studies and highlight the relevance of whole-blood eQTL mapping in prioritization of GWAS candidate genes in humans.


Assuntos
Fenômenos Fisiológicos Sanguíneos/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Reprodutibilidade dos Testes , Transcriptoma
11.
Am J Hum Genet ; 91(4): 754-9, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-23000146

RESUMO

Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.


Assuntos
Proteínas de Transporte/genética , Códon sem Sentido , Ceratodermia Palmar e Plantar/genética , Proteínas Adaptadoras de Transporte Vesicular , Alelos , Cromossomos Humanos Par 15/genética , Exoma , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Queratinócitos/metabolismo , Ceratodermia Palmar e Plantar/metabolismo , Masculino , Linhagem , Biossíntese de Proteínas , RNA Mensageiro/genética , Análise de Sequência de DNA/métodos , Dermatopatias/genética , Dermatopatias/metabolismo
12.
Hum Mol Genet ; 18(12): 2288-96, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19304780

RESUMO

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395,912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.


Assuntos
Pressão Sanguínea , Caderinas/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipertensão/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Hipertensão/fisiopatologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Nat Genet ; 40(8): 946-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18660810

RESUMO

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Síndrome das Pernas Inquietas/genética , Regiões 5' não Traduzidas/genética , Áustria , Canadá , Estudos de Casos e Controles , República Tcheca , Alemanha , Humanos
14.
Nat Genet ; 39(8): 1000-6, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17637780

RESUMO

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.


Assuntos
Predisposição Genética para Doença , Síndrome das Pernas Inquietas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 6 , Grupo com Ancestrais do Continente Europeu/genética , Haplótipos , Proteínas de Homeodomínio/genética , Humanos , Íntrons , MAP Quinase Quinase 5/genética , Pessoa de Meia-Idade , Proteína Meis1 , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Fatores de Transcrição/genética
15.
Am J Hum Genet ; 78(2): 193-201, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16358215

RESUMO

Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.


Assuntos
Cromossomos Humanos Par 9/genética , Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X , Hipercalciúria/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , Animais , Criança , Pré-Escolar , Mapeamento Cromossômico , Análise Mutacional de DNA , Raquitismo Hipofosfatêmico Familiar/classificação , Raquitismo Hipofosfatêmico Familiar/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Ligação Genética , Humanos , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Mutação , Linhagem , Filogenia , Polimorfismo de Nucleotídeo Único
16.
Lancet ; 366(9483): 371-7, 2005 Jul 30-Aug 5.
Artigo em Inglês | MEDLINE | ID: mdl-16054936

RESUMO

BACKGROUND: Familial hemiplegic migraine is an autosomal dominant severe subtype of migraine with aura characterised by some degree of hemiparesis during the attacks. So far, mutations in two genes regulating ion translocation-CACNA1A and ATP1A2-have been identified in pedigrees with this disease. METHODS: To identify additional genes for familial hemiplegic migraine, we did a genome-wide linkage analysis of two disease pedigrees without mutations in CACNA1A and ATP1A2. Ion channel genes in the candidate interval were analysed for mutations, and the functional consequences of the recorded sequence alteration were determined. FINDINGS: We identified a novel locus for familial hemiplegic migraine on chromosome 2q24. Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A, mutations of which have been associated with epilepsy. This same mutation was present in three families with familial hemiplegic migraine. It results in a charge-altering aminoacid exchange in the so-called hinged-lid domain of the protein, which is critical for fast inactivation of the channel. Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated. INTERPRETATION: Dysfunction of the neuronal sodium channel SCN1A can cause familial hemiplegic migraine. Our findings have implications for the understanding of migraine aura. Moreover, our study reinforces the molecular links between migraine and epilepsy, two common paroxysmal disorders.


Assuntos
Cromossomos Humanos Par 2 , Enxaqueca com Aura/genética , Mutação de Sentido Incorreto , Neurônios/metabolismo , Canais de Sódio/genética , Adolescente , Adulto , Idoso , Hemiplegia/complicações , Hemiplegia/genética , Humanos , Pessoa de Meia-Idade , Enxaqueca com Aura/complicações
17.
J Invest Dermatol ; 123(6): 1073-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15610517

RESUMO

Pili annulati, a rare hair shaft abnormality with a characteristic shiny appearance due to alternating light and dark bands of the hair, is assumed to be inherited in an autosomal dominant mode with high penetrance. A locus for pili annulati has not been found yet. We identified one large and four small European kindreds with pili annulati and conducted a genomewide linkage analysis using 382 microsatellite markers. A multipoint logarithm of the odds (LOD) score of 3.19 was demonstrated between D12S1659 and D12S1723 on the telomeric part of the long arm of chromosome 12. Subsequent finemapping in a region of 20 cM gave a maximum multipoint LOD score of 3.24 at D12S1723 under the assumption of homogeneity and a LOD score of 3.57 around D12S343 under the assumption of heterogeneity, both exceed the statistical thresholds necessary to conclude linkage. Most of this LOD score came from the largest family, which reached a maximum LOD score of 3.81. The maximum two-point LOD score for all families was 3.97 at D12S1609. Definite recombination events narrowed the region of shared haplotype in the affected individuals to an 8 Mb region between the marker D12S324 and the telomeric end of the long arm of chromosome 12.


Assuntos
Cromossomos Humanos Par 12 , Doenças do Cabelo/genética , Escore Lod , Mapeamento Cromossômico , Feminino , Cabelo , Cor de Cabelo/genética , Haplótipos , Humanos , Masculino , Linhagem
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