Speculation on the role of transposable elements in human genetic disease with particular attention to achondroplasia and the fragile X syndrome.

We suggest that mutations for fragile X-positive Martin-Bell syndrome, and perhaps also for achondroplasia, may result from the insertion of transposable elements (TE's). Loss of genetic function could result from either the insertion of TE's within or adjacent to a normal chromosomal gene or, in the case of fragile X, from the loss of genes distal to the site of TE insertion following subsequent TE excision without ligation of the resulting discontinuity. The phenotypically and often cytogenetically normal transmitting males in fragile X pedigrees are interpreted not as "nonpenetrant" transmitters of a fully formed fragile X but rather as transmitters of some or all of the factors necessary for TE insertion at Xq27. We consider it likely that such insertion frequently first occurs, both in soma and especially in the germline, in their daughters. Our models predict that father to son transmission of causative factors would be a common occurrence in fragile X pedigrees. The absence of documented father to son transmission either points to a flaw in the models or reflects systematic bias in the collection of pedigree information.

G2 chromosomal radiosensitivity in ataxia telangiectasia lymphocytes.

The peripheral lymphocytes from 7 patients affected with ataxia telangiectasia (AT) were found to be about twice as sensitive to the induction of chromatid-type aberrations by X-rays administered during the G2 phase of the cell cycle as cells from normal controls. Peripheral lymphocytes from 6 AT heterozygotes were no more sensitive than the controls. Using labelling of peripheral lymphocytes with tritiated thymidine, followed by autoradiography, it was determined that cells from affected patients, heterozygotes and normal controls, whether irradiated or not, all had similar percent labeled mitoses (PLM) curves, so the increased induced aberration yields seen in the AT cells is not simply the consequence of a longer than normal G2 phase, nor of G2 delay induced by the radiation. Peripheral lymphocytes from two affected patients and two controls were irradiated in culture, labeled with tritiated thymidine and collected with colcemid over various intervals so that by scoring unlabeled cells in autoradiographs the time course of aberration yield over all of G2 could be determined. The curve for chromatid aberrations for the AT cells differ significantly from that for the controls in intercept, suggesting that in the AT cells the radiation induces more lesions capable of resulting in aberrations, but that their repair may be similar.

G0 chromosomal radiosensitivity in ataxia telangiectasia lymphocytes.

Contrary to an earlier report, peripheral lymphocytes from 4 AT patients were not found to exhibit higher yields of unequivocal chromosome type aberrations following irradiation in the G0 phase of the cell cycle, providing that only first post-irradiation metaphases were included in the samples (ensured by 5-bromodeoxyuridine (BrdU) incorporation and differential fluorescence or Giemsa staining). We were able, however, to confirm the earlier-reported increase in chromatid-type aberrations in the G0-irradiated cells. AT lymphocytes were found to experience more cell-cycle delay following G0 irradiation than normal cells. These observations appear consistent with the damaged base excision DNA-repair defect reported for AT cells.

Double balanced chromosomal translocation carrier (6;8), (13;14)--a case report.

This paper reports the identification of a carrier of two different balanced chromosomal translocations (45,XX,-13,-14, + t(13q;14q), t(6;8) (p11;p12]. Ascertainment occurred during family studies following prenatal diagnosis performed because of advanced maternal age. Family pedigree and past reproductive difficulties also are reviewed, and the theoretical probability of producing a phenotypically normal offspring is explored. We are unaware of previously published observations in which two different balanced autosomal translocations are found in the same individual.

G2 chromosomal radiosensitivity in Fanconi's anemia.

Both the peripheral lymphocytes from 4 patients affected with the inherited disease Fanconi's anemia (FA), and tissue-culture fibroblasts from skin biopsies from 3 patients similarly affected were found to be about twice as sensitive to the induction of chromatid-type chromosomal aberrations by X-rays administratered in the G2 phase of the cell cycle as cells from normal controls. Using tritiated thymidine labelling of peripheral lymphocytes and of cultured fibroblasts, it was determined that 3 affected patients and 3 normal controls all had similar percent labeled mitoses (PLM) curves, so the increased induced aberration yields seen in the FA cells do not appear to be simply a consequences of a longer than normal G2 phase of the cell cycle.

Assignment of the H-Y antigen gene to the short arm of chromosome Y.

We have presented two cases strongly suporting a Y chromosome short-arm location for the H-Y antigen gene. The first case was HY antigen-positive with an isochromosome for the short arm of the Y with no long arm of the Y being present. The other case was H-Y antigen-negative in fibroblasts from an individual with a 46,X,i(Yq) karyotype with no short arm of the Y present. The two cases presented also confirmed previous reports that the testicular forming gene is also located on the short arm of chromosome Y.

The fallability of X-chromatin as a screening test for anomalies of the X chromosome.

In 13 of 148 patients suspected of anomalies of the X chromosome, the X-chromatin test was misleading. Therefore, if an anomaly is suspected, a karyotype as well as an X-chromatin study is indicated.

Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants.

A number of individuals with aberrant Y chromosomes have been tested for the presence of Y-chromosome-specific reiterated DNA. These studies locate Y-chromosome-specific reiterated sequences on the long arm of the Y chromosome. Correlation with phenotype and other known Y chromosome markers establish that the Y-chromosome-specific reiterated DNA discussed here has no evident role in male determination.

Translocation of 9q/13q resulting in duplication (trisomy 9pter leads to 9q22) and deficiency (monosomy 13pter leads to 13q12).

A profoundly retarded, 12-year-old female is described. Her phenotype is compatible with the clinical features of the trisomy 9p syndrome. Cytogenetic analyses showed her to be trisomic for 9pter leads to 9q22 and monosomic for 13pter leads to 13q12, as the result of adjacent-2 segregation during meiosis in her mother. The family pedigree shows this (9;13) translocation to be present in at least three generations.

A 14/14 marker chromosome lymphocyte clone in ataxia telangiectasia.

A lymphocyte clone with a 45, XY karyotype with a 14/14 tandem translocation marker, the frequency of which is time-variable, has been observed in an ataxia telangiectasia patient. Cells with the marker chromotosome were not observed in fibroblasts cultures derived from a skin biopsy, nor was the marker observed in leukocyte cultures from the patient's two affected sibs.