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Biomedical subjects

B Knebelmann

Publications and source records attributed to B Knebelmann.

28 records · Page 2Linked to original sources
PubMed1993

Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young.

Missense and nonsense mutations in the glucokinase gene have recently been shown to result in maturity-onset diabetes of the young (MODY), a subtype of non-insulin-dependent diabetes mellitus with early age of onset. Glucokinase catalyzes the formation of glucose-6-phosphate and is involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Nucleotide sequence analysis of exon 4 and its flanking intronic regions of the glucokinase gene, in four hyperglycemic individuals of a MODY family, revealed a deletion of 15 base pairs, which removed the t of the gt in the donor splice site of intron 4, and the following 14 base pairs. This deletion resulted in two aberrant transcripts, which were analyzed by reverse transcription of RNA from lymphoblastoid cells obtained from a diabetic patient. In one of the abnormal transcripts, exon 5 is missing, while in the other, the activation of a cryptic splice site leads to the removal of the last eight codons of exon 4. This intronic deletion in a donor splice site seems to cause a more severe form of glucose intolerance, compared with point mutations described in glucokinase. This might be due to a more pronounced effect on insulin secretion.

Adult↗
PubMed1992

Autosomal dominant polycystic kidney disease: from molecular genetics to the patients.

One of the gene loci (PKD1) responsible for autosomal dominant polycystic kidney disease was located in 1985 to the short arm of chromosome 16. The clinical consequences of this finding are analyzed. Genetic heterogeneity has been demonstrated since 5%-15% of the families inherit a non-PKD1 mutation. Progress in molecular genetics allows better classification of patients with some atypical manifestations, e.g., those with early renal failure or those with congenital hepatic fibrosis. Identification of the gene(s) and of their defects will provide further progress.

Chromosome Mapping↗
PubMed1992

Alport syndrome and diffuse leiomyomatosis: deletions in the 5' end of the COL4A5 collagen gene.

Alport syndrome (AS) is an hereditary glomerulonephritis that is mainly inherited as a dominant X-linked trait. Structural abnormalities in the type IV collagen alpha 5 chain gene (COL4A5), which maps to Xq22, have recently been detected in several patients with AS. The association of AS with diffuse esophageal leiomyomatosis (DL) has been reported in 24 patients, most of them also suffering from congenital cataract. The mode of transmission and the location of the gene(s) involved in this association have not been elucidated. Southern blotting using cDNA probes spanning the whole COL4A5 and a 5' end COL4A5 genomic probe showed that three out of three patients with the DL-AS association had a deletion in the 5' part of the COL4A5 gene extending beyond its 5' end. This indicates that the same gene, COL4A5, is involved in classical AS and in DL-AS and that the transmission of DL-AS is X-linked dominant. These results also suggest that leiomyomatosis might be due to the alteration of a second gene involved in smooth muscle cell proliferation, which is located upstream of the COL4A5 gene, and that there might be a contiguous gene deletion syndrome, involving at least the genes coding for congenital cataract, DL and AS.

Adolescent↗
PubMed1992

Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.

A large kindred with adult-type X-linked Alport syndrome was studied with regard to a defect in the recently described COL4A5 collagen gene. Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y repeat sequence, is interrupted 22 times by noncollagenous sequences. The mutation creates an additional interruption in the Gly-X-Y repeat motif, between interruptions 4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the triple-helix formation, and, in turn, modifies the ultrastructural and functional characteristics of the type IV collagen network inside the glomerular basement membrane.

Adult↗
PubMed1991

Anti-Müllerian hormone Bruxelles: a nonsense mutation associated with the persistent Müllerian duct syndrome.

The persistent Müllerian duct syndrome (PMDS) is characterized by the persistence of Müllerian derivatives, uterus and tubes, in otherwise normally virilized males. In a previous study, we showed that this syndrome is heterogeneous, with lack of production of anti-Müllerian hormone (AMH) by testicular tissue accounting for only some, AMH-negative, cases of this disorder. We have characterized the point mutation responsible for an AMH-negative PMDS in three siblings: a guanine to thymine transversion at position 2096 in the fifth exon changes a GAA triplet, coding for glutamic acid, to a TAA stop codon. The mutation could also be recognized, using the polymerase chain reaction, on RNA produced in trace amounts by a lymphoblastic cell line. The translation product, although undetectable in testicular tissue, could be visualized in culture medium of cells transfected with the mutant gene.

Anti-Mullerian Hormone↗
PubMed1991

[Molecular biology of normal and pathologic anti-müllerian hormone].

Anti-Müllerian hormone, responsible for Müllerian regression in male fetuses, is a glycoprotein dimer with two 72 kD subunits. The AMH gene is a small (2,800 bp) gene with 5 exons, localized on the tip of the short arm of chromosome 19, band p 133, and transcribed in a 2,000 kbp mRNA. Persistent Müllerian duct syndrome, a rare form of male pseudohermaphroditism characterized by the presence of uterus and Fallopian tubes in patients with normally virilized genitalia, may result from defective AMH gene or from target-organ insensitivity. Four mutations were identified in the AMH gene, 3 are point mutations (2 stop codons, the third altering the secondary structure of the molecule), the last is a 14 bp deletion, leading to alteration of the reading frame of the mRNA.

Anti-Mullerian Hormone↗