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Biomedical subjects

James German

Publications and source records attributed to James German.

5 recordsLinked to original sources
PubMed2006

Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome.

AIMS: To obtain an understanding of the etiology of proportional dwarfism and endocrinopathies of Bloom's syndrome BS. METHODS: Admission for 5-day periods to an NIH-supported Clinical Research Center of a randomly selected population of persons with BS (n = 11; mean age 11.5 years, range 9 months to 28.5 years) for clinical and genetic history-taking, physical examination, and endocrinological, gastroenterological and immunological testing. RESULTS: An oral glucose tolerance test was performed in all participants. Impaired glucose tolerance was present in 4 individuals, insulin resistance was observed in 6 individuals, and previously unrecognized diabetes was found in 1. Growth hormone provocation was normal in the 10 individuals tested. Overnight frequent GH sampling was suggestive of neurosecretory dysfunction in 3. Compensated hypothyroidism was found in 2 participants. Lipid profile abnormalities were present in 5 of 10 individuals. Low immunoglobulin concentrations (IgG and/or IgM) were seen in all tested. Intestinal absorption by D-xylose and/or fecal fat measurement was normal in all individuals tested as well. CONCLUSION: Altered carbohydrate metabolism is very common in BS, and is present from childhood. BS dwarfism is not related to growth hormone deficiency or malabsorption. The basis for the growth restriction in BS remains to be elucidated.

Adolescent↗
PubMed2004

Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.

In addition to increased DNA-strand exchange, a cytogenetic feature of cells lacking the RecQ-like BLM helicase is a tendency for telomeres to associate. We also report additional cellular and biochemical evidence for the role of BLM in telomere maintenance. BLM co-localizes and complexes with the telomere repeat protein TRF2 in cells that employ the recombination-mediated mechanism of telomere lengthening known as ALT (alternative lengthening of telomeres). BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur. Additionally, TRF1 and TRF2 interact directly with BLM and regulate BLM unwinding activity in vitro. Whereas TRF2 stimulates BLM unwinding of telomeric and non-telomeric substrates, TRF1 inhibits BLM unwinding of telomeric substrates only. Finally, TRF2 stimulates BLM unwinding with equimolar concentrations of TRF1, but not when TRF1 is added in molar excess. These data suggest a function for BLM in recombination-mediated telomere lengthening and support a model for the coordinated regulation of BLM activity at telomeres by TRF1 and TRF2.

Adenosine Triphosphatases↗
PubMed2004

Evidence that xeroderma pigmentosum cells do not perform the first step in the repair of ultraviolet damage to their DNA. 1969.

Xeroderma pigmentosum (XP) is a recessively transmitted disorder of man characterized by increased sensitivity to ultraviolet light. Homozygous, affected individuals, upon exposure to sunlight, sustain severe damage to the skin; this damage is characteristically followed by multiple basal and squamous cell carcinomas and not uncommonly by other malignant neoplasia. A tissue culture cell line was derived from the skin of a man with XP. Our measurements of ultraviolet-induced pyrimidine dimers in cellular DNA show that normal diploid human skin fibroblasts excise up to 70 per cent of the dimers 24 hours, but that fibroblasts derived from the individual with XP excise less than 20 per cent in 48 hours. Alkaline gradient sedimentation experiments show that during the 24 hours after irradiation of normal cells a large number of single-stranded breaks appear and then disappear. Such changes are not observed in XP cells. XP cells apparently fail to start, the excision process because they lack the required function of an ultraviolet-specific endonuclease. These findings, plus earlier ones of Cleaver on the lack of repair replication in XP cells, raise the possibility that unexcised pyrimidine dimers can be implicated in the oncogenicity of ultraviolet radiation.

DNA Repair↗
PubMed2002

Enhanced tumor formation in mice heterozygous for Blm mutation.

Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.

Adenoma↗