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Gert Matthijs

Publications and source records attributed to Gert Matthijs.

43 records · Page 3Linked to original sources
PubMed2002

Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation.

GATA1 is the X-linked transcriptional activator required for megakaryocyte and erythrocyte differentiation. Missense mutations in the N-terminal zinc finger (Nf) of GATA1 result in abnormal hematopoiesis, as documented in four families: the mutation V205M leads to both severe macrothrombocytopenia and dyserythropoietic anemia, D218G to macrothrombocytopenia and mild dyserythropoiesis without anemia, G208S to macrothrombocytopenia and R216Q to macrothrombocytopenia with beta-thalassemia. The three first GATA1 mutants display a disturbed binding to their essential transcription cofactor FOG1, whereas the fourth mutant shows an abnormal direct DNA binding. In this study, we describe a new family with deep macrothrombocytopenia, marked anemia and early mortality, if untreated, due to a different GATA1 mutation (D218Y) in the same residue 218 also implicated in the above mentioned milder phenotype. Zinc finger interaction studies revealed a stronger loss of affinity of D218Y-GATA1 than of D218G-GATA1 for FOG1 and a disturbed GATA1 self-association. Comparison of the phenotypic characteristics of patients from both families revealed that platelet and erythrocyte morphology as well as expression levels of the platelet GATA1-target gene products were more profoundly disturbed for the hemizygote D218Y mutation. The D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of a female carrier while her leukocytes showed a skewed X-inactivation pattern. We conclude that the nature of the amino acid substitution at position 218 of the Nf of GATA1 is of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients and possibly also in inducing skewed X inactivation.

Amino Acid Substitution↗
PubMed2002

Pathogenic mutations and rare variants of the APC gene identified in 75 Belgian patients with familial adenomatous polyposis by fluorescent enzymatic mutation detection (EMD).

Familial adenomatous polyposis (FAP) is a dominant inherited colorectal cancer syndrome which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Enzymatic mutation detection (EMD) has potential advantages over the standard protein truncation test (PTT) that is currently used in screening the APC gene for mutations. First we wanted to validate the EMD technique in comparison to PTT. Secondly, we wanted to develop an efficient working protocol for EMD screening of APC. Seventy-five unrelated patients were screened for mutations. All mutations that had previously been detected by PTT were also identified by EMD; the sizes of the cleavage fragments were as expected according to the position of the mutations within the amplicons. A new screening strategy based on EMD allows the analysis of the APC gene in 31 overlapping PCR fragments. In total, EMD efficiently detected the 26 truncating mutations in this series. In addition, two rare variants were also detected: the first is the typical Ashkenazi missense mutation I1307K while the second variant, E1317Q, has been identifed in Belgian patients and controls, and should no longer be considered as a pathogenic mutation, but rather classified as a polymorphism.

Adenomatous Polyposis Coli↗
PubMed2002

DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG).

Since 1997, the molecular basis of six different types of Congenital Disorders of Glycosylation with a defect in the synthesis of N-glycans (CDG-I) has been identified. To assure an efficient molecular diagnosis of the six genes involved in these types, we established a denaturing high-pressure liquid chromatography (DHPLC) screening procedure. Primers were designed and conditions were optimised for the analysis of each exon of the PMM2, MPI, ALG6, ALG3, DPM1 and MPDU1 genes. Forty previously described PMM2 mutations were tested to evaluate the method. All of them could be detected. Hence, the sensitivity of the technique is virtually 100%. Screening of 17 novel cases with a tentative, clinical diagnosis of CDG-Ia identified mutations on both alleles in 14 of them, thereby confirming the diagnosis. Six of these mutations were not previously reported (G15E, G42R, Y64C, E93A, G214S and D223N). Sequencing of the complete coding sequence of PMM2 in the remaining three patients did not reveal mutations, corroborating the good performance of the DHPLC method. A similar DHPLC approach was also applied to CDG-Ib, CDG-Ic, CDG-Id, CDG-Ie and CDG-If samples. New mutations were identified in MPI (Y129C) and ALG6 (G227E). All results were confirmed by sequencing. We conclude that the DHPLC platform is a sensitive and efficient method for the rapid analysis of disease genes with a limited number of exons.

Chromatography, High Pressure Liquid↗
PubMed2002

Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins.

OBJECTIVE: To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment. STUDY DESIGN: Nine North American patients with CDG type I and different ethnic origins were studied. RESULTS: All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients. CONCLUSIONS: The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.

Congenital Disorders of Glycosylation↗
PubMed2002

Congenital disorders of glycosylation: a review.

Congenital disorders of glycosylation (CDGs) are a rapidly growing group of inherited disorders caused by defects in the synthesis and processing of the asparagine(ASN)-linked oligosaccharides of glycoproteins. The first CDG patients were described in 1980. Fifteen years later, a phosphomannomutase deficiency was found as the basis of the most frequent type, CDG-Ia. In recent years several novel types have been identified. The N-glycosylation pathway is highly conserved from yeast to human, and the rapid progress in this field can largely be attributed to the systematic application of the knowledge of yeast mutants. Up to now, eight diseases have been characterized, resulting from enzyme or transport defects in the cytosol, endoplasmic reticulum, or Golgi compartment. CDGs affect all organs and particularly the CNS, except for CDG-Ib, which is mainly a hepatic-intestinal disease.

Animals↗
PubMedDate not supplied

Tetrasomy 12pter-12p13.31 in a girl with partial Pallister-Killian syndrome phenotype.

A dysmorphic patient was shown to carry a small supernumerary marker chromosome. Multicolor, centromere-multicolor and regular FISH experiments proved the marker to be an analphoid 12pter derived isochromosome. Microdissection of the marker followed by reverse painting and array CGH analysis showed that the isochromosome contains approximately 6 Mb of 12pter-12p13.31 derived sequence. This is only the second report of a marker with a neocentromere 12pter and the molecular fine mapping of the duplicated region further refines the 12p region defining the Pallister-Killian syndrome phenotype. In addition, we show the feasibility of using microdissected chromosomes or chromosomal fragments to molecularly map the chromosomal breakpoints on array CGH. This technology may aid in the identification of chromosomal translocation breakpoints.

Abnormalities, Multiple↗