James German

The Bloom's syndrome gene product is homologous to RecQ helicases

The Blooms syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.

Bloom Syndrome: A Mendelian Prototype of Somatic Mutational Disease

Spontaneous mutations in human somatic cells occur far more often than normal in individuals with Bloom syndrome. The basis for understanding these mutations and their developmental consequences emerges from examination of BS at the molecular, cellular, and clinical levels. The major clinical feature of BS, proportional dwarfism, as well as its major clinical complication, an exceptionally early emergence of neoplasia of the types and sites that affect the general population, are attributable to the excessive occurrence of mutations in somatic cells. Here, the following aspects of BS are discussed: (i) the BS phenotype; (ii) neoplasia in BS, including the means--the Blooms Syndrome Registry--by which the significant risk for diverse sites and types of cancer in these patients was revealed; (iii) the biological basis for the cancer proneness of BS; and, finally, (iv) the significance for both basic human biology and clinical medicine of BS as the prototype of somatic mutational disease.

Bloom’s Syndrome

D1Z2 is a highly polymorphic DNA locus composed of a tandem of repetitive units. Its molecular constitution has been examined in 61 clonal cell lines selected at random from two lymphoblastoid cell lines (LCLs), each of which had been proliferating in vitro for several hundred days. Thirty-three of the cells were selected from an LCL derived from the blood of a person with Blooms syndrome (BS), and the others from a normal person. A total of 20 distinctive band alterations in D1Z2 were observed, all in BS cells: appearance of a novel band(s); disappearance of a band(s), or alterations in the intensity of a band(s). Unequal sister-chromatid exchange giving rise to intra-locus mutation is considered the most plausible explanation for the accumulation of the changes detected.

Chromosomal Breakage in a Rare and Probably Genetically Determined Syndrome of Man

A high frequency of chromosomal breakage and rearrangement has been found in cultured blood cells from six of seven individuals with a rare syndrome characterized by congenital telangiectatic erythema and stunted growth. Only 19 instances of this apparently genetically determined disorder are known, and malignant neoplasia has developed in three.

Bloom's syndrome. XX. The first 100 cancers.

As of 1996 the 100th cancer was diagnosed in Blooms syndrome. The cancers have been regularly documented since 1960 in a program of surveillance referred to as the Blooms Syndrome Registry. Tabulated here are their types and ages of onset. The 100 cancers arose in 71 of the 168 registered individuals. Represented in Blooms syndrome are both the cancers that commonly affect the general population and the rare tumors of early childhood. This body of information has become sufficiently large to be useful to geneticists and physicians in advising affected families concerning cancer risk. Of more general significance, however, the distribution of cancer sites and types sets Blooms syndrome apart from other cancer-predisposing genetically determined conditions, affirming its experimental value as a model for analyzing the nonenvironmental component in the etiology of the generality of human cancer.

Cytological Evidence for Crossing-Over in vitro in Human Lymphoid Cells

In human blood cells dividing in vitro two chromosomes are occasionally found intimately associated in a quadriradial configuration (Qr). A Qr by traditional interpretation is the result of chromatid interchange. Since the configurations in blood cells often are equal and symmetrical and are composed of homologous chromosomes, they are considered cytological evidence that somatic crossing-over may occur in mammalian cells.

Bloom's syndrome. III. Analysis of the chromosome aberration characteristic of this disorder

Chromatid interchange between somatic chromosomes, a phenomenon occasionally observed in normal lymphocytes in culture, occurs with a greatly increased frequency in Blooms syndrome lymphocytes. Highly characteristic interchanges occur at apparently homologous sites on homologous chromosomes and affect certain regions preferentially.

The Roberts syndrome

The Roberts syndrome consists of tetraphocomelia, cleft lip/palate, and prominence of the phallus. This paper summarizes the major phenotypic abnormalities of 17 previously reported cases and reports five new cases. The features to be considered in the diagnosis of the Roberts syndrome arc: (1) tetraphocornelia with ectrodactyly and syndactyly, (2) cleft lip/palate with protrusion of the intermaxillary portion of the upper jaw, (3) ocular hypertelorism, (4) prominence of the phallus, (5) cryptorchidism in the male, and (6) intra‐ and extra‐uterine growth retardation. Analysis of pedigrees suggests autosomal recessive inheritance. The morphologic appearance of the metaphasc chromosomes in one case was unusual and unexplained.

Chromosomal Breakage and Acute Leukemia in Congenital Telangiectatic Erythema and Stunted Growth

Excerpt Investigation of unusual and unexplainable aspects of leukemia may lead toward further understanding of malignant neoplasia. This is a report of three individuals with a rare and only recen...

Bloom's syndrome and Fanconi's anemia: Demonstration of two distinctive patterns of chromosome disruption and rearrangement

SummaryA comparison of the patterns of chromosome breakage and rearrangements was made using lymphocytes from one patient with Blooms syndrome and one with Fanconis anemia. Chromatid and isochromatid gaps and breaks were increased in frequency in both conditions. In Fanconis anemia, more aberrations per aberrant cell occurred than in Blooms syndrome. The relative numbers of the various classes of interchanges and the chromosome regions affected differed strikingly. In Blooms syndrome, homologous chromosomes had formed most of the interchanges, while in Fanconis anemia non-homologous chromosomes were preferentially involved in the interchanges. The patterns formed by brakage, including breaks involved in interchanges, show a non-random distribution of the lesions in both conditions.