Biomedical subjects

M J Abramowicz

Publications and source records attributed to M J Abramowicz.

24 records · Page 2Linked to original sources

PubMed1994

Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.

Isodisomy (ID) is a genetic anomaly defined as the inheritance of two copies of the same genetic material from one parent. ID in an offspring is a rare cause of recessive genetic diseases via inheritance of two copies of a mutated gene from one carrier parent. We studied a newborn female with a mut(o) of methylmalonic acidemia and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus. The patient died 2 wk after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal ID, involving at least a 25-centiMorgan portion of the chromosome pair that encompasses the MHC. ID probably caused methylmalonic acidemia by duplication of a mutated allele of the corresponding gene on the chromosome 6 inherited from the father. It is also very likely that ID was etiologically related to the agenesis of beta cells and consequent insulin-dependent diabetes mellitus in our patient. We thus speculate on the existence of a gene on chromosome 6 involved in beta cell differentiation.

Amino Acid Metabolism, Inborn Errors↗

PubMed1992

Functional study of the human thyroid peroxidase gene promoter.

Structure/function relationships in the human thyroid peroxidase gene promoter have been studied by deletion and mutation analyses and confronted with footprint patterns obtained with thyroid nuclear extracts and the purified thyroid transcription factor TTF-1. Crude nuclear extracts from dog thyroid primary cultures were shown to contain a binding activity recognizing the -119 to -105 segment of the promoter (coordinates relative to the transcriptional start site). Deletion, or site-directed mutagenesis of this segment dramatically reduced transcriptional activity in transient expression experiments on gene fusions of the thyroid peroxidase promoter and the growth hormone reporter. This binding activity was increased in nuclear extracts from thyrocytes cultured in the presence of the cAMP-agonist forskolin. A mutation that decreased the promoter function in forskolin-stimulated thyrocytes resulted in weakening of the corresponding footprint. The binding site displays no significant sequence similarities with known cAMP-responsive elements. Mutagenesis of another region of the promoter (-99 to -94) induced the binding of an additional factor, resulting in a dramatically enhanced promoter activity. We show that the thyroid-specific transcriptional factor TTF-1 is not directly involved in the above-mentioned interactions and provide evidence suggesting that, in spite of displaying a similar binding pattern to thyroperoxidase and thyroglobulin promoters in vitro, TTF-1 plays a less important role in the former. Altogether, our data delineate the minimal thyroid peroxidase gene promoter in the human and identify the binding sites of two trans-activating factors, one of them being potentially the mediator of a non-conventional cAMP control, independent of the cAMP-responsive element and factor AP-2.

Animals↗

PubMed1992

Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Thyroid peroxidase (TPO) is the key enzyme in the synthesis of thyroid hormones, and the TPO defects are believed to be the most prevalent causes of the inborn errors of thyroid metabolism. We investigated an adopted boy with iodide organification defect, who presented with florid hypothyroidism at the age of 4 mo, poorly complied with thyroxine treatment, and developed a compressive goiter necessitating partial resection at the age of 12 yr. Biochemical studies revealed the absence of TPO activity in the resected tissue. Genomic DNA studies identified a 4 base-pair insertion in the eighth exon of the TPO gene, and showed that the patient was homozygous for this frameshift mutation. The direct genetic diagnosis of this mutation can be made by digestion of polymerase chain reaction products with NaeI restriction enzyme. This will help assessing its prevalence among the heterogenous genetic group of TPO defects.

Amino Acid Sequence↗

PubMed1992

Tumour-like presentation of pulmonary sarcoidosis.

We report a case of pulmonary sarcoidosis, which initially presented as a left apical infiltrate. The later course mimicked a pulmonary neoplasm, with left upper lobe atelectasis secondary to bronchial stenosis, resulting from both endobronchial sarcoidosis and extrinsic compression by enlarged lymph nodes. Extrinsic pressure from sarcoid nodes on the left main pulmonary artery and recurrent laryngeal nerve, also caused a reduction in pulmonary parenchymal perfusion and left vocal cord paresis.

Diagnosis, Differential↗

PubMed1990

Thyroid peroxidase gene promoter confers TSH responsiveness to heterologous reporter genes in transfection experiments.

The cyclic AMP-mediated transcriptional regulation of the enzyme thyroperoxidase by thyrotropin (TSH) in thyroid follicular cells was examined at the molecular level. The 5' end of the human thyroperoxidase gene was isolated and sequenced and the transcription start site was mapped by S1 nuclease analysis. A 0.9 kilobase pair DNA fragment of the promoter was shown to confer responsiveness to thyrotropin, and cyclic AMP, in transient expression assays using two different reporter genes. Several potential sites for specific interaction with nuclear transcription factors which could be involved in the regulation of thyroperoxidase gene transcription were identified.

Animals↗

PubMedDate not supplied

[Molecular diagnosis of hereditary diseases].

Molecular biology has produced important achievements in research, and provides useful applications to the clinical field. This is true today in diagnostics, and will be true in therapeutics tomorrow. The identification of pathogenic mutations through direct analysis of known genes allows diagnoses to be reached in a growing number of disorders. When mutations cannot be identified, familial linkage studies using polymorphic molecular markers will reach a diagnosis indirectly, most of the times. This is useful either presymptomatically or prenatally. The identification of genetic risk factors in targeted populations is becoming a means of prevention of multifactorial diseases. This approach opens a very large field of applications of molecular genetics in clinical practice. Basic concepts of molecular genetics are briefly reviewed, and the principles of diagnostics in hereditary diseases are approached via a few representative examples.

Adenomatous Polyposis Coli↗