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Martijn H Breuning

Publications and source records attributed to Martijn H Breuning.

At least 19 recordsLinked to original sources
PubMed2007

Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is associated with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. OBJECTIVE: To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. RESULTS: The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically observed in patients with RSTS. CONCLUSIONS: Part of the clinical variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.

Adult↗
PubMed2006

Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.

Peters Plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, and developmental delay. After detection of a microdeletion by array-based comparative genomic hybridization, we identified biallelic truncating mutations in the beta 1,3-galactosyltransferase-like gene (B3GALTL) in all 20 tested patients, showing that Peters Plus is a monogenic, primarily single-mutation syndrome. This finding is expected to put Peters Plus syndrome on the growing list of congenital malformation syndromes caused by glycosylation defects.

Adult↗
PubMed2006

Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation.

CONTEXT: GH insensitivity can be caused by defects in the GH receptor (GHR) or in the postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary and immunological problems were described with a defect in STAT5b, a critical intermediary of downstream GHR signaling. OBJECTIVE: The objective was to determine the functional characteristics of a novel STAT5b mutation and describe the phenotype. PATIENT: We describe an adult male patient with short stature [-5.9 sd score (SDS)], delayed puberty, and no history of pulmonary or immunological problems. GH-binding protein level as well as GH secretion characteristics were normal. Plasma prolactin level was elevated. Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found. RESULTS: We found a homozygous frameshift mutation in the STAT5b gene (nucleotide 1102-3insC, Q368fsX376), resulting in an inactive truncated protein, lacking most of the DNA binding domain and the SH2-domain. CONCLUSIONS: This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommended.

Adult↗
PubMed2006

An XX male with the sex-determining region Y gene inserted in the long arm of chromosome 16.

OBJECTIVE: To report a case of a 46,XX male with an insertion of the sex-determining region Y (SRY) region in the terminal end of the long arm of chromosome 16. DESIGN: Case report. SETTING: Molecular and cytogenetic units in a university hospital. PATIENT(S): An infertile male, with normal masculinization of the external genitalia, who was referred for chromosomal analysis as an unaffected member of a family with idiopathic hypertrophic osteoarthropathy. INTERVENTION(S): Cytogenetic investigation, physical examination, and hormonal assays. MAIN OUTCOME MEASURE(S): Chromosomal analysis using GTG banding and fluorescence in situ hybridization (FISH). RESULT(S): Conventional chromosome analysis revealed a normal 46,XX karyotype. The FISH with bacterial artificial chromosomes (BACs) of the SRY region indicated the presence of this region on the terminal end of the long arm of chromosome 16. CONCLUSION(S): This is the first case of a 46,XX male with the SRY gene present on an autosome-here chromosome 16. The size of the inserted region containing SRY, inserted in 16qter, is approximately 600 kb.

Chromosome Mapping↗
PubMed2006

A complex rearrangement on chromosome 22 affecting both homologues; haplo-insufficiency of the Cat eye syndrome region may have no clinical relevance.

The presence of highly homologous sequences, known as low copy repeats, predisposes for unequal recombination within the 22q11 region. This can lead to genomic imbalances associated with several known genetic disorders. We report here a developmentally delayed patient carrying different rearrangements on both chromosome 22 homologues, including a previously unreported rearrangement within the 22q11 region. One homologue carries a deletion of the proximal part of chromosome band 22q11. To our knowledge, a 'pure' deletion of this region has not been described previously. Four copies of this 22q11 region, however, are associated with Cat eye syndrome (CES). While the phenotypic impact of this deletion is unclear, familial investigation revealed five normal relatives carrying this deletion, suggesting that haplo-insufficiency of the CES region has little clinical relevance. The other chromosome 22 homologue carries a duplication of the Velocardiofacial/DiGeorge syndrome (VCFS/DGS) region. In addition, a previously undescribed deletion of 22q12.1, located in a relatively gene-poor region, was identified. As the clinical features of patients suffering from a duplication of the VCFS/DGS region have proven to be extremely variable, it is impossible to postulate as to the contribution of the 22q12.1 deletion to the phenotype of the patient. Additional patients with a deletion within this region are needed to establish the consequences of this copy number alteration. This study highlights the value of using different genomic approaches to unravel chromosomal alterations in order to study their phenotypic impact.

Abnormalities, Multiple↗
PubMed2006

Transgenic mice expressing tamoxifen-inducible Cre for somatic gene modification in renal epithelial cells.

Gene inactivation often leads to an embryonic-lethal phenotype. In focal diseases like renal cell carcinomas and polycystic kidney disease, somatic gene inactivation in subsets of cells is likely to occur at later stages. We generated a transgenic mouse line with an inducible form of Cre recombinase for conditional gene modifications in kidney epithelial cells. To this end a 1.4-kb promoter fragment of the kidney-specific cadherin gene (KspCad) was cloned upstream of a tamoxifen-inducible Cre recombinase (CreER(T2)) encoding sequence. Expression and activity of Cre was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) analysis and by crossbreeding to Z/EG reporter mice. One KspCad-CreER(T2) line showed kidney-specific Cre expression and mediated recombination upon tamoxifen treatment in Z/EG reporter mice. No reporter gene expression was detected in untreated animals or in extrarenal tissues upon treatment. Within the kidneys, enhanced green fluorescent protein (EGFP) fluorescence was observed in epithelial cells in several nephronic segments. In addition, the system successfully recombined a floxed Pkd1 gene.

Animals↗
PubMed2006

Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications.

Duplicons, that is, DNA sequences with minimum length 10 kb and a high sequence similarity, are known to cause unequal homologous recombination, leading to deletions and the reciprocal duplications. In this study, we designed a Multiplex Amplifiable Probe Hybridisation (MAPH) assay containing 63 exon-specific single-copy sequences from within a selection of the 169 regions flanked by duplicons that were identified, at a first pass, in 2001. Subsequently, we determined the frequency of chromosomal rearrangements among patients with developmental delay (DD) and/or congenital malformations (CM). In addition, we tried to identify new regions involved in DD/CM using the same assay. In 105 patients, six imbalances (5.8%) were detected and verified. Three of these were located in microdeletion-related regions, two alterations were polymorphic duplications and the effect of the last alteration is currently unknown. The same study population was tested for rearrangements in regions with no known duplicons nearby, using a set of probes derived from 58 function-selected genes. The latter screening revealed two alterations. As expected, the alteration frequency per unit of DNA is much higher in regions flanked by duplicons (fraction of the genome tested: 5.2%) compared to regions without known duplicons nearby (fraction of the genome tested: 24.5-90.2%). We were able to detect three novel rearrangements, including the previously undescribed reciprocal duplication of the Williams Beuren critical region, a subduplicon alteration within this region and a duplication on chromosome band 16p13.11. Our results support the hypothesis that regions flanked by duplicons are enriched for copy number variations.

Child↗
PubMed2006

Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).

BACKGROUND & AIMS: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. METHODS: We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer, we performed immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. RESULTS: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. CONCLUSIONS: We show that heterozygous truncating mutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with absent staining for the PMS2 protein.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease characterized by enlarged kidneys and congenital hepatic fibrosis. Given the poor prognosis for the majority of children with the severe perinatal ARPKD phenotype, there is a regular request for prenatal testing. ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which consists of 86 exons that are variably assembled into a number of alternatively spliced transcripts. The longest transcript, comprising 67 exons, encodes the protein fibrocystin/polyductin. We have set up mutation analysis by direct sequencing of these 67 exons. In 39 mainly Dutch families we identified: 11 nonsense mutations, 15 deletions/insertions, 5 splice site mutations, and 39 missense mutations. To classify missense variants we combined evolutionary conservation, using the human, chimpanzee, dog, mouse, chicken and frog Pkhd1 sequences, with the Grantham score for chemical differences. Thirty-three missense mutations were considered pathogenic and seven were classified as rare, probably pathogenic variants. In addition to sequence analysis, multiplex ligation-dependent probe amplification (MLPA) was used to identify multiple exon deletions. However, no large deletions in the PKHD1 gene were identified. In 31 index patients two mutations were found, in 6 patients one mutation was found, leading to a mutation detection rate of 87%. The analysis of amino acid conservation as well as applying the Grantham score for chemical differences allowed us to determine the pathogeneity for nearly all new missense mutations and thus proved to be useful tools to classify missense variants.

Amino Acid Sequence↗
PubMed2005

Increased activity of activator protein-1 transcription factor components ATF2, c-Jun, and c-Fos in human and mouse autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease is a common inherited disorder that predominantly manifests with the formation of fluid-filled cysts in both kidneys. The disease can be accounted for by a mutation in either the PKD1 or the PKD2 gene. It was demonstrated previously that aberrant expression of the PKD1 gene product, polycystin-1, results in modification of activator protein-1 (AP-1) transcription factor activity in cultured renal epithelial cells. Here, it is reported that activity of the AP-1 components c-Jun, ATF2, and c-Fos is altered in renal cystic tissue of patients with autosomal dominant polycystic kidney disease and of hypomorphic Pkd1 mice with polycystic kidney disease. Data were obtained using immunohistochemical and Western blot analysis. Significant upregulation of Thr71- and Thr69/71-phosphorylated ATF2 and Ser73-phosphorylated c-Jun and increased c-Fos were detected in small cysts and (dilated) ducts and tubules surrounded by fibrotic interstitium. The data indicate that various AP-1 components are constitutively activated in polycystic kidney disease and suggest that aberrant AP-1 activity is relevant for cyst formation.

Activating Transcription Factor 2↗
PubMed2005

Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease.

CREB-binding protein and p300 function as transcriptional coactivators in the regulation of gene expression through various signal-transduction pathways. Both are potent histone acetyl transferases. A certain level of CREB-binding protein is essential for normal development, since inactivation of one allele causes Rubinstein-Taybi syndrome (RSTS). There is a direct link between loss of acetyl transferase activity and RSTS, which indicates that the disorder is caused by aberrant chromatin regulation. We screened the entire CREB-binding protein gene (CBP) for mutations in patients with RSTS by using methods that find point mutations and larger rearrangements. In 92 patients, we were able to identify a total of 36 mutations in CBP. By using multiple ligation-dependent probe amplification, we found not only several deletions but also the first reported intragenic duplication in a patient with RSTS. We extended the search for mutations to the EP300 gene and showed that mutations in EP300 also cause this disorder. These are the first mutations identified in EP300 for a congenital disorder.

Acetyltransferases↗
PubMed2005

Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis.

We have designed Multiplex Amplifiable Probe Hybridization (MAPH) probes for 28 exons of the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD. The set was used to screen DNA from limb-girdle muscular dystrophy (LGMD) patients for the presence of pathogenic deletion or duplication mutations. An unexpected heterozygous deletion of SGCG exon 7 was detected in a patient from a consanguineous family in which a known c.525delT mutation segregates. The exon 7 deletion was inherited from the father, who was part of the consanguineous c.525delT branch of the family but who did not carry the c.525delT mutation. A similar, homozygous deletion had been identified in two unrelated LGMD patients from southern Italy. The deletion breakpoints were mapped, isolated, and sequenced, and were identical in all cases. Haplotype analysis showed the same alleles segregating with the mutation in all three patients, suggesting a common ancestor. Exonic deletions in sarcoglycanopathies appear to be rare events. However, we recommend screening for exonic deletions/duplications in patients where a mutation has not been identified in both alleles, as well as in seemingly homozygous cases where segregation of the mutations can not be confirmed in the parents.

Alleles↗
PubMed2005

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations.

Multiple osteochondromas (MO) is an autosomal dominant condition, caused by mutations in either the EXT1 or the EXT2 gene. The DNA of a cohort of 35 patients, clinically suspected to be affected with MO, was screened for mutations by a combination of direct sequence analysis and multiplex ligation-dependent probe amplification (MLPA). In this cohort, 26 pathogenic gene alterations were found (74%). With sequence analysis mutations were detected in 22 patients (63%). In total, 10 mutations were detected in the EXT1 and 12 in the EXT2 gene. The number of the splice site mutations detected was larger than expected from the literature. In addition, with the MLPA four deletions of one or more exons were found in this cohort. Two patients, of whom one had a negative family history, showed deletions of exon 1 of the EXT1 gene, which is possibly a deletion hot spot. In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes.

Cohort Studies↗
PubMed2005

Common regulatory elements in the polycystic kidney disease 1 and 2 promoter regions.

The PKD1 and PKD2 genes are mutated in patients with autosomal dominant polycystic kidney disease (ADPKD), a systemic disease, with the formation of renal cysts as main clinical feature. The genes are developmentally regulated and aberrant expression of PKD1 or PKD2 leads to cystogenesis. To date, however, the transcription factors regulating expression of these genes have hardly been studied. To identify conserved putative transcription factor-binding sites, we cloned and characterized the 5'-flanking regions of the murine and canine Pkd1 genes and performed a multispecies comparison by including sequences from the human and Fugu rubripes orthologues as well as the Pkd2 promoters from mouse and human. Sequence analysis revealed a variety of conserved putative binding sites for transcription factors and no TATA-box element. Nine elements were conserved in the mammalian Pkd1 promoters: AP2, E2F, E-Box, EGRF, ETS, MINI, MZF1, SP1, and ZBP-89. Interestingly, six of these elements were also found in the mammalian Pkd2 promoters. Deletion studies with the mouse Pkd1 promoter showed that a approximately 280 bp fragment is capable of driving luciferase reporter gene expression, whereas reporter constructs containing larger fragments of the Pkd1 promoter showed a lower activity. Furthermore, mutating a potential E2F-binding site within this 280 bp fragment diminished the reporter construct activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the Pkd1 gene. Our data define a functional promoter region for Pkd1 and imply that E2F, EGRF, Ets, MZF1, Sp1, and ZBP-89 are potential key regulators of PKD1 and PKD2 in mammals.

5' Flanking Region↗
PubMed2005

What's the message? Interpretation of an uninformative BRCA1/2 test result for women at risk of familial breast cancer.

PURPOSE: To test the "false-reassurance hypothesis," which suggests that women who receive an uninformative BRCA1/2 test result may incorrectly conclude that they no longer have an elevated risk, with possible harmful consequences for adherence to breast surveillance guidelines. METHODS: A prospective questionnaire design was used to compare 183 women with an uninformative BRCA test result (94 affected and 89 unaffected) with 41 proven BRCA mutation-carriers and 49 true negatives before and after BRCA1/2 test disclosure. RESULTS: After DNA-test disclosure, test applicants differed from each other with regard to their perception of the likelihood of carrying a deleterious gene (P < 0.0001). The BRCA mutation carriers reported the highest perceived likelihood and the true negatives reported the lowest. Compared to the predisclosure measures, women who received an uninformative DNA test result reported a lower perceived risk after disclosure (P < 0.0001), suggesting a relatively high level of reassurance because of the test result. However, after DNA-test disclosure, only 12 women concluded that the risk of carrying a mutation was nonexistent, and perceived likelihood was significantly associated with the pedigree-based risk assessment (P = 0.0001). Moreover, despite the significant decrease in perceived likelihood for uninformative women, intention to obtain mammograms did not change (P = 0.71); it remained at the same almost optimal level as for BRCA mutation carriers. CONCLUSION: No support was found for the suggestion that the nature of uninformative test results is often misunderstood. Moreover, an uninformative test result did not affect the positive mammography intentions of both affected and unaffected women.

Adaptation, Psychological↗
PubMed2004

Three new families with arterial tortuosity syndrome.

Arterial tortuosity syndrome (ATS) is a rare condition with autosomal recessive inheritance characterized by connective tissue abnormalities. The most specific clinical findings are cardiovascular anomalies including tortuosity, lengthening, aneurysm, and stenosis formation of major arteries. Also ventricular hypertrophy is frequently present. Other anomalies are skin hyperextensibility and cutis laxa, joint laxity or contractures of the joints, and inguinal herniae. Histology shows disruption of elastic fibers of the media. These features suggest that ATS is a connective tissue disorder. A biochemical or molecular defect has not yet been identified. We describe here nine additional ATS patients from three consanguineous Moroccan families and review a total of 35 patients with this uncommon condition.

Abnormalities, Multiple↗