Variability of aortic stiffness is not associated with the fibrillin 1 genotype in patients with Marfan's syndrome.
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Adult↗
Biomedical subjects
G Pals
Publications and source records attributed to G Pals.
Vascular type of Ehlers-Danlos syndrome in a patient with ruptured aneurysm of the splenic artery.
A 39-year-old woman presented with a ruptured aneurysm of the splenic artery. The postoperative course was complicated by poor wound healing. This, in combination with a history of easy bruising and joint hypermobility, made us consider a connective tissue disease as underlying cause. The vascular type of Ehlers-Danlos syndrome was diagnosed by identifying collagen III deficiency and the corresponding gene mutation in cultured fibroblasts from a skin biopsy.
Adult↗
Genome-wide linkage in three Dutch families maps a locus for abdominal aortic aneurysms to chromosome 19q13.3.
OBJECTIVES: Elucidation of the genetic background of familial abdominal aortic aneurysm (AAA) suggests a genetic etiology. METHODS AND RESULTS: We carried out a genome-wide scan in three Dutch families with four or five affected siblings. Suggestive loci were further studied by subsequent fine mapping of the locus performed in 101 affected sib-pairs. The genome-wide scan was performed with 400 DNA markers and results were given as non-parametric, multipoint linkage scores (NPL). We observed a suggestive linkage for AAA (NPL score 3.25 at D19S902, 72.72 cM) on chromosome 19q in the three families. After fine mapping on chromosome 19, the NPL score became nominal in the 101 affected sib-pairs. A separate analysis of the three families with fine mapping revealed a peak with significant evidence for linkage (NPL score 3.95 at D19S904, 78.08 cM) on chromosome 19q. This peak was situated to the right compared to the region found in a previously published article for familial AAA on chromosome 19q. CONCLUSIONS: Our results identified a candidate locus in three Dutch families with AAA at chromosome 19q13.3. Separate analysis of these three families provides evidence for genetic heterogeneity.
Aged↗
A novel BRCA2 mutation in an Indonesian family found with a new, rapid, and sensitive mutation detection method based on pooled denaturing gradient gel electrophoresis and targeted sequencing.
BACKGROUND: Breast cancer is increasing in Indonesia and other developing countries. Germline mutations in the BRCA1/2 genes are most strongly associated with a high risk for breast cancer development. There have been no reports on BRCA1/2 gene mutations in the Indonesian population. Genetic research yielding insight into mutations affecting the Indonesian population can help in risk assessment of individual patients. AIMS: To screen the BRCA1/2 genes for mutations in early onset Indonesian breast cancer patients and their families with a new, simple, and sensitive BRCA1/2 mutation screening strategy based on denaturing gradient gel electrophoresis (DGGE) and targeted sequencing. METHODS: DNA was isolated from the blood of four Indonesian breast cancer patients from high risk families and seven family members, and the polymerase chain reaction was performed with specially designed primers throughout the BRCA1/2 coding sequences to produce fragments suitable for pooled DGGE analysis. The aberrantly migrating samples were reamplified and sequenced. RESULTS: Two mutations were found in exons 13 and 16 of BRCA1 and two mutations in exons 2 and 14 of BRCA2, which turned out to be established polymorphisms according to the Breast Cancer Information Core. In addition, a novel 6 bp deletion in exon 11, leading to a premature stop, was found in BRCA2. CONCLUSION: Pooled DGGE and targeted sequencing revealed four BRCA1/2 polymorphisms and one novel BRCA2 mutation in a group of Indonesian patients at high risk of hereditary breast cancer. This illustrates that the proposed method is sensitive and particularly suited for screening unknown populations.
Adult↗
DNA copy number changes at 8q11-24 in metastasized colorectal cancer.
BACKGROUND: C-Myc, a well-known oncogene located on 8q24.12-q24.23, is often amplified and over-expressed in both primary and metastasizing colorectal cancer. In addition, PRL-3 (also known as PTP4A3), a tyrosine phosphatase located on 8q24.3, is amplified in colorectal cancer metastasis. Beside PRL-3 and c-myc, other oncogenes located on the 8q23-24 region might be involved in this process. Therefore, the present study aims to correlate DNA copy number status of a series of genes at 8q23-24 in colorectal cancer at high resolution in correlation to metastatic disease. MATERIALS AND METHODS: Thirty-two cases of colorectal cancer, 10 stage B1, 10 B2 and 12 D (Astler-Coller) with their corresponding liver metastasis and one colorectal cell line (colo205, previously analyzed by array-CGH), were included in this study. A chromosome 8 specific MLPA probe mixture was used to analyze the presence of DNA copy number changes. The probe mixture contained 29 probes covering 25 genes on chromosome 8, as well as 6 control probes on other chromosomes. RESULTS AND DISCUSSION: MLPA results obtained of the colo205 colorectal cell line were comparable with previous array-CGH results, thus validating the MLPA probe mixture. Astler-Coller B1 and B2 colorectal cancers differed significantly in DNA copy number of the genes, MOS (p=0.04), MYC (p=0.007), DDEF1 (p=0.004), PTK2 (p=0.02) and PTP4A3 (p=0.04). When comparing these with Astler-Coller D primary tumors, significant differences were seen for several genes as well (MYC (p<0.000), DDEF1 (p<0.000), SLA (p<0.000), PTK2 (p<0.000), PTP4A3 (p=0.002), and RECQL4 (p=0.01)). When comparing primary Astler-Coller D tumors and their corresponding liver metastases, a similar pattern of gains and losses was observed. Most of the liver metastases showed higher DNA copy number ratios than the corresponding primary tumors, but this difference was only significant for TPD52 (p=0.02) and EIF3S6 (p=0.007). CONCLUSION: In addition to c-myc, multiple genes on chromosome 8 differed significantly between primary colorectal cancers with and without liver metastases. This observation is consistent with the concept that clinical behaviour, like risk of liver metastasis, is determined by the genomic profile that is already present in the primary tumor.
Base Sequence↗
Heterogeneous basis of the type VIB form of Ehlers-Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation.
Skin fibroblasts from the majority of patients with the clinical diagnosis of Ehlers-Danlos syndrome type VI (EDS VI; kyphoscoliosis type), have significantly decreased lysyl hydroxylase (LH) activity due to mutations in the LH1 gene (classified as EDS VIA: OMIM no. 225400). A rare condition exists in which patients are clinically similar but have normal levels of LH activity (designated EDS VIB: OMIM no. 229200). To define the biochemical defect, we have examined cultured fibroblasts from four EDS VIB patients for changes in the levels of the mRNAs for LH1, LH2, and LH3, collagen cross-linking patterns, and the extent of lysine hydroxylation of type I collagen alpha chains. Although normal levels of LH1 mRNA were observed in all four patients, in two patients the levels of LH2 mRNA were decreased by >50%, and a similar decrease was observed in LH3 mRNA in the other two patients. A distinct pattern of collagen cross-links, indicative of decreased lysyl hydroxylation, could be identified in EDS VIA patients, but there was no clear correlation between collagen cross-link pattern and changes in the individual LH mRNAs in EDS VIB patients. Linkage to tenascin-X was excluded in these patients. This study suggests that the basis for this form of EDS VI is genetically heterogeneous, and that alternative pathways in addition to lysine hydroxylation of collagen may be affected.
Cell Line↗
Genome-wide linkage in a large Dutch consanguineous family maps a locus for intracranial aneurysms to chromosome 2p13.
BACKGROUND AND PURPOSE: Familial occurrence of intracranial aneurysms suggests a genetic factor in the development of these aneurysms. In this study, we present the identification of a susceptibility locus for the development of intracranial aneurysms detected by a genome-wide linkage approach in a large consanguineous pedigree. METHODS: Patients with clinical signs and symptoms of intracranial aneurysms, confirmed by radiological, surgical, or postmortem investigations, were included in the study. Magnetic resonance angiography was used to detect asymptomatic aneurysms in relatives. RESULTS: Seven out of 20 siblings had an intracranial aneurysm. Genome-wide multipoint linkage analysis showed a significant logarithm of the odds score of 3.55. CONCLUSIONS: In a large consanguineous pedigree intracranial aneurysms are linked to chromosome 2p13 in a region between markers D2S2206 and D2S2977.
Chromosome Mapping↗
Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome.
In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical Marfan syndrome (MFS) and to study possible phenotypic differences between patients with an FBN1 mutation vs. without, a comprehensive molecular study of the FBN1 gene in a cohort of 93 MFS patients fulfilling the clinical diagnosis of MFS according to the Ghent nosology was performed. The initial mutation screening by CSGE/SSCP allowed identification of an FBN1-mutation in 73 patients. Next, sequencing of all FBN1-exons was performed in 11 mutation-negative patients, while in nine others, DHPLC was used. This allowed identification of seven and five additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in one more patient. A total of 23 out of the 85 mutations identified here are reported for the first time. Phenotypic comparison of MFS patients with cysteine-involving mutations vs. premature termination mutations revealed significant differences in ocular and skeletal involvement. The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history. Most likely, a portion of FBN1-mutations remains undetected because of technical limitations. In conclusion, the involvement of the FBN1-gene could be demonstrated in at least 91% of all MFS patients (85/93), which strongly suggests that this gene is the predominant, if not the sole, locus for MFS.
Adolescent↗
Apparent absence of BRCA2 protein in a proportion of acute myeloid leukemia cell lines.
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Acute Disease↗
Ehlers-Danlos syndrome type IV: unusual congenital anomalies in a mother and son with a COL3A1 mutation and a normal collagen III protein profile.
A mother and son with Ehlers-Danlos syndrome (EDS) type IV and unusual congenital anomalies are described. The congenital anomalies include, in the mother, amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephaly and, in the son, an esophageal atresia and hydrocephaly. Protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities. However, DNA analysis of the COL3A1 gene revealed a pathogenic mutation (388G-->T) in both the mother and the son. The possible relationship between the observed congenital anomalies and EDS IV are discussed. We stress that DNA analysis of COL3A1 should be performed in all patients when there is a strong suspicion of EDS IV, despite negative findings in a collagen protein analysis.
Collagen Type III↗
Anticipation in familial intracranial aneurysms in consecutive generations.
Intracranial aneurysms (IA) are the major cause of subarachnoid haemorrhages (SAH). A positive family history for SAH is reported in 5-10% of the patients. The mode of inheritance is not unambiguously established; both autosomal dominant and recessive modes have been reported. In sporadic as well as in familial SAH, approximately 60% of the SAH patients are female. Recently, anticipation has been described in familial SAH. Since up to 15% of the SAHs are not caused by an IA, we have analysed anticipation, sex ratio and mode of inheritance only in families with patients with a proven IA in two consecutive generations. A total of 10 families were studied in which at least two persons in consecutive generations were affected by SAH, a symptomatic IA (SIA) or a presymptomatic IA (PIA). We also analysed published data from families with a proven IA in two consecutive generations on age of SIA onset and sex ratios among affected family members (both SIA and PIA). The age of SIA onset in the parental generation (mean 55.5 years) differed significantly from the age of onset in their children (mean 32.4 years). In the parental generation 11 men and 37 women were affected (both SIA and PIA), in the consecutive generation these numbers were 28 men and 32 women. There is a significant difference in sex ratio of affected family members when the generations are compared (P<0.02). No family could be found in which three consecutive generations were affected by an IA (SIA or PIA).
Adult↗
Expression of differentiation and proliferation related proteins in epithelium of prophylactically removed ovaries from women with a hereditary female adnexal cancer predisposition.
AIMS: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium. METHODS: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR). RESULTS: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected. CONCLUSIONS: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.
Adnexal Diseases↗
Genetic linkage of candidate genes in families with abdominal aortic aneurysms?
OBJECTIVES: to examine possible involvement of several candidate genes in the aetiology of familial abdominal aortic aneurysm (AAA). DESIGN: after reviewing the literature on the genetics of familial AAA, betaine homocysteine methyltransferase (BHMT), collagen type Ialpha2 (COL1A2) and cathepsin H (CTSH), were selected as potential candidate genes, which influence structure, strength, elasticity and mechanical resistance of the aortic wall. MATERIALS: forty-eight families with 110 family members and AAA were included in the affected sib-pair analysis. One large family of three generations was analysed separately because in this family also other clinical symptoms were involved. METHODS: genetic linkage analysis was performed with DNA markers in the region of BHMT, COL1A2 and CTSH. RESULTS: In the overall sib-pair analysis, the LOD scores for BHMT, COL1A2 and CTSH were 0.7, 0.2 and -0.7, whereas in the large family these numbers were -0.6, -2.2 and -2.7, respectively. CONCLUSIONS: none of the candidate genes selected showed a suggestive linkage with AAA. Exclusion of the COL1A2 and CTSH genes was possible in the large family that was analysed separately.
Aortic Aneurysm, Abdominal↗
Two Dutch families with hereditary hyperferritinaemia-cataract syndrome and heterozygosity for an HFE-related haemochromatosis gene mutation.
Hereditary haemochromatosis is an autosomal recessive disorder, leading to progressive iron overload, which is very common among the Caucasian population. In the vast majority of the cases, the hereditary iron overload is caused by mutations in the HFE gene. Most prominently this is the homozygous Cys282Tyr mutation. We report two Dutch families in which both propositi were found to be heterozygous for Cys282Tyr in the work-up of hyperferritinaemia. Frequent phlebotomies had no effect on the ferritin level, but led to microcytic anaemia. Finally, the family history with bilateral cataracts was the clue for the correct diagnosis. Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disease characterised by elevated serum ferritin levels and bilateral cataracts in the absence of iron overload. Several point mutations and deletions within the iron-responsive element (IRE) in the 5' noncoding region of the L-ferritin gene have been found in HHCS families. In the first Dutch family a G to C transition at position 32 was found and a G to A mutation at the same location was found in the second Dutch family. In individuals with an isolated hyperferritinaemia (normal transferrin saturation), the presence of early onset (familial) cataract should raise the possibility of HHCS, even when Cys282Tyr heterozygosity is found.
Cataract↗
Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach.
Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.
Adaptor Proteins, Signal Transducing↗
[From gene to disease; craniosynostosis syndromes due to FGFR2-mutation].
One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene. Upon ligand binding the FGFR2 receptors dimerise, and this is followed by activation of the intracellular tyrosine kinase domains. This initiates a cascade of signals that influence cell division and differentiation. FGFR2 mutations have been found in the Apert, Crouzon and Pfeiffer craniosynostosis syndromes. Most mutations are gain of function mutations, inducing ligand-independent receptor activation or altered ligand binding. With the exception of Apert syndrome, there is no clear genotype-phenotype correlation. Many different mutations have been found in Pfeiffer and Crouzon syndrome, but all of the mutations occur in the same extracellular region of the receptor. Identical mutations have been found in Pfeiffer and Crouzon syndrome. So within one family, both Crouzon and Pfeiffer syndrome may occur. Mutations in other FGFR-genes have also been found in craniosynostosis syndromes.
Acrocephalosyndactylia↗
Familial abdominal aortic aneurysm: a systematic review of a genetic background.
BACKGROUND: Familial clustering of the abdominal aortic aneurysm (AAA) is clear, 12-19% of AAA patients have one or more first-degree relatives with an aneurysm and 4-19% is detected with ultrasound screening. OBJECTIVES: To review the genetic background of AAA. DESIGN, METHODS AND MATERIALS: Computer searches of the MEDLINE, EMBASE, SUMsearch database and the Cochrane Library and searched reference lists of English language articles concerning the genetics of AAA, candidate gene approach and linkage analysis. RESULTS: Brothers of AAA patients are at high risk to develop an AAA. The candidate gene approach was performed to detect defects in one of the components of the connective tissue, i.e. type I and III collagen, elastin and fibrillin, the inflammatory cell-derived matrix metalloproteinase, there inhibitors, auto-immune components and components related to atherosclerosis. CONCLUSION: These studies give us insight in the pathology but do not lead to the specific genetic factor(s) responsible for (familial) AAA. Considering the supposed autosomal dominant inheritance, a gene mutation in one of the structural proteins of the connective tissue is expected. In the future, linkage analysis may resolve the genetic background of AAA.
Aortic Aneurysm, Abdominal↗
Linkage and association studies of IL1B and IL1RN gene polymorphisms in preeclampsia.
OBJECTIVE: To determine whether preeclampsia is either associated with or linked to two polymorphisms in the IL1B gene (IL1B-TaqI and IL1B-511) and one polymorphism in the IL1RN gene (IL1RN-IVS2). METHODS: Genotyping was performed in 150 affected sib-pair families and 104 healthy Dutch blood donors. Genotype and allele frequencies as well as allelic associations were assessed in three groups of unrelated women from these 150 families; 133 with either eclampsia, preeclampsia or the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, 101 with preeclampsia only, and 63 with HELLP syndrome only. These frequencies were compared to those in controls. Frequencies of transmitted and nontransmitted haplotypes, inferred from the three polymorphisms, were compared. Allele sharing between affected siblings from all 150 families was assessed by means of multipoint nonparametric affected sib-pair analyses. RESULTS: No significant differences in genotype and allele frequencies were found between the unrelated study groups and controls. No allelic associations were apparent, nor were there differences in frequencies of transmitted and nontransmitted haplotypes within affected families. Excess allele sharing for any of the three polymorphic markers was absent in affected sib-pairs. CONCLUSIONS: None of the IL1B and IL1RN polymorphisms provided evidence for either association or linkage with the risk for (pre)eclampsia/HELLP syndrome, preeclampsia only or HELLP syndrome only.
Female↗