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2.
BMC Med Genet ; 18(1): 50, 2017 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-28468609

RESUMO

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, pear-shaped nose and cone shaped epiphyses. This condition is caused by haploinsufficiency of the TRPS1 gene. Previous genotype-phenotype studies have correlated exon 6 missense mutations with TRPS type III, a severe form of type I with pronounced, facial characteristics, short stature and brachydactyly and differing from type II by the absence of exostoses and mental retardation. CASE PRESENTATION: We report the first case of a Moroccan family, a father and his three children, in which the diagnosis of type III TRPS was suspected based on severe clinical and radiological features. Molecular analysis of the TRPS1 gene revealed a novel missense mutation in exon 6, (p.Ala932Ser), located in the GATA-type DNA-binding zinc finger domain. CONCLUSION: Our observations in this kindred support the previous genotype-phenotype results suggesting that patients with more pronounced facial characteristics and more severe shortening of hands and feet are more likely to have mutation in exon 6 of TRPS1.


Assuntos
Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Marrocos , Linhagem , Proteínas Repressoras , Adulto Jovem
3.
Clin Genet ; 86(3): 220-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24128419

RESUMO

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.


Assuntos
Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Predisposição Genética para Doença/genética , Cinesinas/genética , Proteínas Oncogênicas/genética , Fenótipo , Anormalidades Múltiplas/patologia , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Exoma/genética , Genes Recessivos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Dados de Sequência Molecular , Mutação/genética
4.
Br J Cancer ; 107(8): 1399-408, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22976800

RESUMO

BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. RESULTS: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 µM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). CONCLUSION: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Cerebelares/genética , Reparo de Erro de Pareamento de DNA/genética , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Meduloblastoma/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Linhagem Celular Tumoral , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Criança , Pré-Escolar , Metilases de Modificação do DNA/biossíntese , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/biossíntese , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Proteína 1 Homóloga a MutL , Proteínas Nucleares/biossíntese , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Temozolomida , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética
5.
Colorectal Dis ; 14(9): e562-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22672595

RESUMO

AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.


Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais/genética , Síndrome do Hamartoma Múltiplo/genética , PTEN Fosfo-Hidrolase/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Pólipos do Colo/etiologia , Neoplasias Colorretais/etiologia , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/complicações , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
6.
Clin Genet ; 79(1): 79-85, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21091464

RESUMO

Submicroscopic chromosomal anomalies play an important role in the aetiology of intellectual disability (ID) and have been shown to account for up to 10% of non-syndromic forms. We present a family with two affected boys compatible with X-linked inheritance of a phenotype of severe neurodevelopmental disorder co-segregating with a deletion in Xp22.11 exclusively containing the PTCHD1 gene. Although the exact function of this gene is unknown to date, the structural overlap of its encoded patched domain-containing protein 1, the transmembrane protein involved in the sonic hedgehog pathway, and its expression in human cortex and cerebellum as well as in mice and drosophila brain suggests a causative role of its nullisomy in the developmental phenotype of our family. Our findings support the recent notions that PTCHD1 may play a role in X-linked intellectual disability (XLID) and autism disorders.


Assuntos
Cromossomos Humanos X , Genes Ligados ao Cromossomo X , Deficiência Intelectual , Receptores de Superfície Celular/genética , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Criança , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Receptores Patched , Linhagem , Fenótipo , Deleção de Sequência , Adulto Jovem
7.
Br J Cancer ; 102(6): 1068-73, 2010 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-20160730

RESUMO

BACKGROUND: The target substrates of DNA mismatch recognising factors MutSalpha (MSH2+MSH6) and MutSbeta (MSH2+MSH3) have already been widely researched. However, the extent of their functional redundancy and clinical substance remains unclear. Mismatch repair (MMR)-deficient tumours are strongly associated with microsatellite instability (MSI) and the degree and type of MSI seem to be dependent on the MMR gene affected, and is linked to its substrate specificities. Deficiency in MSH2 and MSH6 is associated with both mononucleotide and dinucleotide repeat instability. Although no pathogenic MSH3 mutations have been reported, its deficiency is also suggested to cause low dinucleotide repeat instability. METHODS: To assess the substrate specificities and functionality of MutSalpha and MutSbeta we performed an in vitro MMR assay using three substrate constructs, GT mismatch, 1 and 2 nucleotide insertion/deletion loops (IDLs) in three different cell lines. RESULTS: Our results show that though MutSalpha alone seems to be responsible for GT and IDL1 repair, MutSalpha and MutSbeta indeed have functional redundancy in IDL2 repair and in contrast with earlier studies, MutSbeta seems to exceed MutSalpha. CONCLUSION: The finding is clinically relevant because the strong role of MutSbeta in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/fisiologia , Repetições de Dinucleotídeos/genética , Proteína 2 Homóloga a MutS/fisiologia , Conformação de Ácido Nucleico , Animais , Células Cultivadas , Proteínas de Ligação a DNA/genética , Células HCT116 , Células HeLa , Humanos , Mutação INDEL/genética , Proteína 2 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS , Mutação de Sentido Incorreto/fisiologia , Spodoptera , Especificidade por Substrato
8.
Colorectal Dis ; 12(10 Online): e243-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20105204

RESUMO

AIM: The study aimed to describe genetical and clinical features of attenuated familial adenomatous polyposis (AFAP) and to propose clinical criteria and guidelines for treatment and surveillance. METHOD: A questionnaire study was carried out of polyposis registries with data on patients with presumed AFAP, defined as having ≤ 100 colorectal adenomas at age ≥ 25. RESULTS: One hundred and ninety-six patients were included. The median number of adenomas was 25 (0-100) with a uniform distribution of colorectal adenomas and carcinomas (CRC). Age at CRC diagnosis was delayed by 15 years compared with classic FAP. Eighty-two patients had a colectomy and an ileorectal anastomosis and 5/82 (6%) had a secondary proctectomy. The location of the mutation in the APC gene was known in 69/171 (40%) tested patients. Only 15/29 (52%) of mutations in APC were found in parts of the gene usually associated with AFAP (the 5' end, exon 9 and 3' end). CONCLUSIONS: A subset of FAP patients with a milder phenotype does exist and treatment and surveillance had to be modified accordingly. The mutation detection rate is lower than in classic FAP and mutations in AFAP patients are located throughout the APC gene. We propose the following clinical diagnostic criteria for AFAP: a dominant mode of inheritance of colorectal adenomatosis and <100 colorectal adenomas at age 25 or older. Colonoscopy had to be preferred to sigmoidoscopy and surveillance had to be life-long. In the majority of patients, prophylactic colectomy and ileorectal anastomosis are recommended at the age of 20-25 years.


Assuntos
Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Sistema de Registros , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colectomia , Análise Mutacional de DNA , Feminino , Genes APC , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estatísticas não Paramétricas , Adulto Jovem
9.
Br J Cancer ; 102(1): 151-61, 2010 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19935791

RESUMO

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). CONCLUSIONS: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.


Assuntos
Adenocarcinoma/química , Neoplasias Colorretais/química , Proteínas Serina-Treonina Quinases/análise , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/química , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno , Variações Dependentes do Observador , Panitumumabe , Valor Preditivo dos Testes , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Distribuição Aleatória , Reprodutibilidade dos Testes , Transdução de Sinais/genética
10.
Fam Cancer ; 9(2): 109-15, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19763885

RESUMO

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Europa (Continente)/epidemiologia , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Diretrizes para o Planejamento em Saúde , Humanos , Anamnese , Proteína 2 Homóloga a MutS/genética , Mutação , Linhagem , Fatores de Risco
11.
Clin Genet ; 74(6): 502-12, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18700894

RESUMO

Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-alpha2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin-alpha2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750-1713_7899-2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin-alpha2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.


Assuntos
Laminina/genética , Distrofias Musculares/congênito , Distrofias Musculares/genética , Polimorfismo Genético , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Deleção de Genes , Humanos , Lactente , Masculino , Mutação , Adulto Jovem
12.
J Perinatol ; 27(3): 181-2, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17314987

RESUMO

Fetal death is not commonly associated with cystic fibrosis (CF). We report a case of late intrauterine death attributed to cardiovascular failure and shock consequent to malrotation and intestinal volvulus in a fetus affected with CF. An argument is made that CF promoted this deleterious incident. Whole blood or cell-rich tissue specimens should be preserved and genetic testing for CF considered in stillbirths with intestinal complications.


Assuntos
Fibrose Cística/complicações , Morte Fetal/etiologia , Autopsia , Criança , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Feminino , Humanos , Volvo Intestinal/complicações , Gravidez , Terceiro Trimestre da Gravidez
13.
Gut ; 55(10): 1440-8, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16461775

RESUMO

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein. METHODS AND RESULTS: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5' Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes ("third hits") in some polyps. We found that the "third hit" probably initiated tumorigenesis. Somatic mutation spectra were similar in 5' and 3' mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, "third hits" were more common. Most "third hits" left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele. CONCLUSIONS: We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need "three hits" however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.


Assuntos
Polipose Adenomatosa do Colo/genética , Mutação em Linhagem Germinativa/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
15.
Eur J Hum Genet ; 12(5): 365-71, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-14735163

RESUMO

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.


Assuntos
Polipose Adenomatosa do Colo/genética , Cromossomos Humanos Par 1/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Fatores Etários , Idoso , Mapeamento Cromossômico , DNA Glicosilases/genética , Saúde da Família , Feminino , Ligação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Linhagem , Penetrância , Fenótipo , Suíça
16.
Ther Umsch ; 60(8): 455-61, 2003 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-14502852

RESUMO

First trimester risk screening is probably the major methodological advance in identifying pregnancies at increased risk for genetic disease during recent years with an impact on all pregnancies. The high detection rate with moderate false positive rates will reduce the over-all number of invasive procedures as compared to the traditional approach based on maternal age exclusively, in particular considering the demographic shift towards higher mean maternal age. Non-invasive prenatal diagnosis from fetal cells or DNA in the maternal circulation remains an experimental approach, despite a growing number of reports on successful diagnoses of single gene disorders. In the lab molecular cytogenetic approaches have considerably broadened the diagnostic spectrum of conventional karyotyping and facilitated a rapid diagnosis of selected frequent aneuploidies. Molecular genetic testing, in particular on chorionic villi, allows an early and reliable diagnosis of a growing number of severe monogenic conditions. A restrictive legislation has hampered the development of preimplantation genetic diagnosis in German speaking countries, only a few groups work on polar body diagnosis, a legal but restricted alternative.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Diagnóstico Pré-Natal , Adulto , Amniocentese , Aneuploidia , Amostra da Vilosidade Coriônica , Aberrações Cromossômicas , Citogenética , Feminino , Aconselhamento Genético , Humanos , Recém-Nascido , Cariotipagem , Idade Materna , Mutação , Gravidez , Primeiro Trimestre da Gravidez , Fatores de Risco , Ultrassonografia Pré-Natal
17.
Am J Hum Genet ; 72(5): 1261-7, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12696020

RESUMO

The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.


Assuntos
Polipose Adenomatosa do Colo/genética , Cromossomos Humanos Par 15/genética , Ligação Genética , Haplótipos/genética , Judeus/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 6/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Escore Lod , Masculino , Linhagem
18.
Proc Natl Acad Sci U S A ; 99(26): 16910-5, 2002 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-12486240

RESUMO

In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at APC. We determined whether colorectal adenomas with two mutations at APC show features consistent with these models by studying 55 lesions (average size 5 mm; range 1-13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at APC is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes APC mutations in tumorigenesis. Regarding the model in which APC mutations lead directly to CIN, if APC mutations do have this effect in vivo, it must be subtle. Alternatively, CIN associated with APC mutations might be essentially an in vitro phenomenon.


Assuntos
Adenoma/genética , Aberrações Cromossômicas , Neoplasias Colorretais/genética , Genes APC , Mutação , Humanos , Antígeno Ki-67/análise , Perda de Heterozigosidade
19.
J Med Genet ; 39(5): 323-7, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12011148

RESUMO

BACKGROUND: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in white populations. These are referred to as A and G types with reference to the A/G polymorphism at IVS14-19. On the basis of preliminary experimental data, we hypothesised that deviations from the expected frequency of these two haplotypes could exist in carriers of disease associated MLH1 germline mutations. METHODS: We assembled a series (n=119) of germline MLH1 mutation carriers in whom phase between the haplotype and the mutation had been conclusively established. Controls, without cancer, were obtained from each contributing centre. Cases and controls were genotyped for the polymorphism in IVS14. RESULTS: Overall, 66 of 119 MLH1 mutations occurred on a G haplotype (55.5%), compared with 315 G haplotypes on 804 control chromosomes (39.2%, p=0.001). The odds ratio (OR) of a mutation occurring on a G rather than an A haplotype was 1.93 (95% CI 1.29 to 2.91). When we compared the haplotype frequencies in mutation bearing chromosomes carried by people of different nationalities with those seen in pooled controls, all groups showed a ratio of A/G haplotypes that was skewed towards G, except the Dutch group. On further analysis of the type of each mutation, it was notable that, compared with control frequencies, deletion and substitution mutations were preferentially represented on the G haplotype (p=0.003 and 0.005, respectively). CONCLUSION: We have found that disease associated mutations in MLH1 appear to occur more often on one of only two known ancient haplotypes. The underlying reason for this observation is obscure, but it is tempting to suggest a possible role of either distant regulatory sequences or of chromatin structure influencing access to DNA sequence. Alternatively, differential behaviour of otherwise similar haplotypes should be considered as prime areas for further study.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Estudos de Casos e Controles , Cromossomos , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Europa (Continente) , Frequência do Gene , Triagem de Portadores Genéticos , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Proteína 1 Homóloga a MutL , América do Norte , Proteínas Nucleares
20.
Proc Natl Acad Sci U S A ; 99(5): 2954-8, 2002 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-11867715

RESUMO

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Genes APC/fisiologia , Adenoma/genética , Neoplasias Colorretais/genética , Primers do DNA , Éxons , Deleção de Genes , Testes Genéticos/métodos , Humanos , Reação em Cadeia da Polimerase/métodos
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