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A partial mechanism for centromeric suppression
140
HUMAN GENETICS SOCIETY OF AUSTRALASIA
Pathology (1980), 12, January
inherited syndrome of osseous fragility with sclerae of normal hue. The frequency of presenile hearing loss in patients with 0.1. type 111 and type IV is not known. These observations on the heterogeneity in osteogenesis imperfecta suggest that different patterns of histological, histochemical, ultrastructural and biochemical abnormalities may be found in these different 0.1. types. THE ABNORMALITIES OF LIPOPROTEIN METABOLISM IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA
E. D. JANUS,ANNEM. NICOLL,P. R. TURNER, R. WOOTTON & B. LEWIS Department of Chemical Pathology and Metabolic Diseases, St Thomas’ Hospital, London, England Familial hypercholesterolaemia (FH) occurs in an estimated 0.1-0.2% of the population. There is autosomal dominant transmission of the disorder and approximately 50% of affected males have coronary heart disease by age 50. Homozygotes rarely survive beyond their twenties. Studies of lipoprotein metabolism were performed in 14 patients with heterozygous FH and 7 control subjects using injections of autologous I 3 l l labelled very low density lipoprotein (VLDL) and 1251 labelled low density lipoprotein (LDL). In normal subjects VLDL-B peptide synthetic rates varied from 10.3-17.1 mg/kg/24 h (mean 15.1 mg/kg/24 h), LDL-B peptide synthetic rates from 5.2-10.3 mg/kg/24 h (mean 7.7 mg/kg/24 h) and LDL-B peptide fractional catabolic rates (FCR) from 0.245-0.36/d (mean 0.31/d). In heterozygous FH VLDL production was normal in 8 patients with normal triglyceride levels. There was either VLDL overproduction or a catabolic defect in 5 patients with superadded hypertriglyceridaemia. LDL-B peptide synthetic rates range from high normal to markedly increased (8.85-18.0 mg/kg/24h) and LDL-B peptide FCR values were markedly reduced (0.135-1.275/d) thus confirming the known LDL catabolic defect and indicating superadded over-production. In a further study LDL-B peptide production from VLDL-B peptide was estimated in 24 subjects using deconvolution analysis of ‘’’I LDL and 1311 LDL-B peptide activity curves. LDL-B peptide production from VLDL-B peptide and directly measured LDL-B peptide production were essentially equal in 6 normal control subjects and in normocholesterolaemic patients. In 6 patients with FH, LDL-B peptide turnover exceeded LDL-B peptide production from VLDL-B peptide, suggesting direct secretion of up to 50% of the LDL in the patients with this condition. CYTOGENETIC PATTERNS IN ACUTE NON-LYMPHOCYTIC LEUKAEMIA
P. NOLAN,G. SZELAG, J . LYALL,L. GIBSON& 0. M. GARSONCytogenetic Unit, University of Melbourne, Departmenl of Medicine, St Vincent’s Hospital, Fitzroy, Vicioria Chromosome banding studies of the leukaemic cells of patients with acute non-lymphocytic leukaemia (A.N.L.L.) show that both numerical and structural changes occur in 50-60% of patients examined at diagnosis. Identification of chromosomes involved in both types of change indicate that there is a non-random involvement of specific chromosomes. In addition, cytogenetic subgroups can be identified which appear to have prognostic implications. This paper reviews the results of chromosome studies in A.N.L.L.performed in thecytogenetic research unit at St St Vincent’s Hospital, from 1975 to 1978. Using short-term marrow cultures, chromosome studies were carried out on 168 patients at diagnosis; 102 were found to have abnormal karyotypes and 48 showed no chromosome abnormality. No mitoses were obtained from 18 patients. To date trypsin G-banding studies have been satisfactorily performed on 47, of whom 37 had abnormalities. The most common abnormality was trisomy 8. A specifictranslocation between 8 and 21 was identified in 3 patients and a 9;22 translocation in 2 others. All patients with acute erythroleukaemia, and the majority with A.N.L.L. occurring after long-term therapy for other haematological disorders, had abnormal karyotypes with multiple abnormalities. The response of these patients to therapy was poor, whereas those with specific translocations all achieved remission. Ten of 12 patients considered to have a preleukaemic syndrome showed chromosome abnormalities which were most frequently monosomy 7 or partial deletion of the long arms ofchromosome 5,(5q-). Similar findings have been reported in other series, but the frequency of Occurrence appears to show geographical variation. Therefore as cytogenetic patterns seem to have diagnostic, prognostic and aetiological implications in A.N.L.L., chromosome studies should always be performed at diagnosis. A PARTIAL MECHANISM FOR CENTROMERIC SUPPRESSION
Aur DANIELCytogenetrcs Unit, Prince of Wales Hospital, Randwick. New South Wales Of constderable surprise and interest to human cytogeneticists with the advent of chromosome banding, has been the number and diversity of dicentric structural rearrangements. These have been found in sex chromosomal and
ABSTRACTS OF ANNUAL MEETING
1979 141
autosomal isochromosomes, Robertsonian translocations, tandem translocations, bisatellited markets and fusion translocations. In Lima-de-Faria‘s model of the centromere, the relationship between the centromeric chromomeres and the kinetochore was unknown. On the supposition that Cd banding stains the kinetochores, a model for the centromere and centromeric suppression is proposed. FAMILIAL STUDIES ON NOR’S
DIANACHAMBERS, MALCOLM PARSLOW & MARGARET DRUMMONDDepartment of Comnzunity Health, School of Medicine, University of Auckland, New Zealand The technique of combined G-banding and silver-nitrate staining of nucleolar organizer regions (NOR’s) allows study of the presence and activity of NOR’s on specific chromosome sites. We have previously reported on the clinical and cytogenetic study of a family with a translocation t(l2;21) (pl 1;pll) where the NOR from the der (21) appears to be translocated onto the der( 12).The original analyses of the NOR’s by silver staining suggested that this site was positive in some carriers and negative in others. The activity ofthis der( 12) NOR has been further studied in repeat blood and skin fibroblast cultures to determine whether this inactivity is a ‘real’ phenomenon or due to cultural or staining differences. The results suggest that there is suppression of the der( 12) NOR in some carrier members of the family and that the satellite association of this chromosome is related to the activity of its NOR. THE EFFECTS OF m-AMSA ON LYMPHOCYTES
CAROLOLDFIELDCytogenetics Unit, Christchurch Hospital, New Zealand The antitumour drug, m-AMSA inhibits the progression of lymphocytes through the cell cycle. This is demonstrated by microdensitometry and the sister chromatid exchange technique. THE EFFECTS OF ,!I RADIATION ON SISTER CHROMATID EXCHANGES IN CULTURED HUMAN LYMPHOCYTES
PETERE. CROSSEN & WILLIAMF. MORGAN Cancer Society of’ New Zealand, Cytogenetics Unit,
Christchurch Hospital, New Zealand The incidence of Sister Chromatid Exchanges (SCE’s) due to radiation was investigated in cultured human lymphocytes using the BrdU/Giemsa technique. Cultures treated continuously with 0,001 and 0.01 pCi of 3HUridine showed no increase in either chromosome abnormalities or SCEs. Continuous treatment with 0.1pCi resulted in a significant increase in chromosome aberrations but no increase in SCE’s while treatment with 0.2 pCi gave both an increase in chromosome aberrations and SCE’s. Cultures given a 4 h pulse with 1.O pCi showed a significant increase in both SCE’s and chromosome aberrations. The results indicate that low levels of fl radiation do not cause an increase in SCEs in human lymphocytes, and that a number, ifnot all, of the exchanges observed at low levels of ,!I radiation with autoradiography, may be spontaneous events. X CHROMOSOME DELETION AND SHORT STATURE
R. L. SHAW The Princess Mary Hospitalfor Children, Auckland. New Zealand The idea that females with monosomy for the short arm of the X chromosome always have short stature was proposed in about 1960,then challenged about10 years later. It seems that little has subsequently been written about this apparent conflict. Examination of data from published cases of Xp-, Xq- and partial Xp monosomy resulting from X chromosome translocations suggests that the original hypothesis was correct, and that the critical locus is situated near-terminally on Xp. EXPERIENCE WITH FRA(X) (q27) IN RETARDED MALES AND CARRIER FEMALES
GRANTR. SUTHERLAND Cytogenetics Unit, Adelaide Children’s Hospital, South Australia The fragile site at Xq27 is associated with X-linked mental retardation with macro-orchidism. This fragile site has been studied in 21 retarded males. Chromosome studies on 11 obligate carrier females have demonstrated the site in only 3 of them. As carriers become older the fragile site becomes more difficult to demonstrate. Amongst 10 young daughters of obligate carriers, 5 have been shown to carry the fragile site. Cytogenetic carrier detection of this form of X-linked mental retardation appears to be fairly reliable in females aged less than 20-25 yr, but is unreliable after this age.
HUMAN GENETICS SOCIETY OF AUSTRALASIA
Pathology (1980), 12, January
inherited syndrome of osseous fragility with sclerae of normal hue. The frequency of presenile hearing loss in patients with 0.1. type 111 and type IV is not known. These observations on the heterogeneity in osteogenesis imperfecta suggest that different patterns of histological, histochemical, ultrastructural and biochemical abnormalities may be found in these different 0.1. types. THE ABNORMALITIES OF LIPOPROTEIN METABOLISM IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA
E. D. JANUS,ANNEM. NICOLL,P. R. TURNER, R. WOOTTON & B. LEWIS Department of Chemical Pathology and Metabolic Diseases, St Thomas’ Hospital, London, England Familial hypercholesterolaemia (FH) occurs in an estimated 0.1-0.2% of the population. There is autosomal dominant transmission of the disorder and approximately 50% of affected males have coronary heart disease by age 50. Homozygotes rarely survive beyond their twenties. Studies of lipoprotein metabolism were performed in 14 patients with heterozygous FH and 7 control subjects using injections of autologous I 3 l l labelled very low density lipoprotein (VLDL) and 1251 labelled low density lipoprotein (LDL). In normal subjects VLDL-B peptide synthetic rates varied from 10.3-17.1 mg/kg/24 h (mean 15.1 mg/kg/24 h), LDL-B peptide synthetic rates from 5.2-10.3 mg/kg/24 h (mean 7.7 mg/kg/24 h) and LDL-B peptide fractional catabolic rates (FCR) from 0.245-0.36/d (mean 0.31/d). In heterozygous FH VLDL production was normal in 8 patients with normal triglyceride levels. There was either VLDL overproduction or a catabolic defect in 5 patients with superadded hypertriglyceridaemia. LDL-B peptide synthetic rates range from high normal to markedly increased (8.85-18.0 mg/kg/24h) and LDL-B peptide FCR values were markedly reduced (0.135-1.275/d) thus confirming the known LDL catabolic defect and indicating superadded over-production. In a further study LDL-B peptide production from VLDL-B peptide was estimated in 24 subjects using deconvolution analysis of ‘’’I LDL and 1311 LDL-B peptide activity curves. LDL-B peptide production from VLDL-B peptide and directly measured LDL-B peptide production were essentially equal in 6 normal control subjects and in normocholesterolaemic patients. In 6 patients with FH, LDL-B peptide turnover exceeded LDL-B peptide production from VLDL-B peptide, suggesting direct secretion of up to 50% of the LDL in the patients with this condition. CYTOGENETIC PATTERNS IN ACUTE NON-LYMPHOCYTIC LEUKAEMIA
P. NOLAN,G. SZELAG, J . LYALL,L. GIBSON& 0. M. GARSONCytogenetic Unit, University of Melbourne, Departmenl of Medicine, St Vincent’s Hospital, Fitzroy, Vicioria Chromosome banding studies of the leukaemic cells of patients with acute non-lymphocytic leukaemia (A.N.L.L.) show that both numerical and structural changes occur in 50-60% of patients examined at diagnosis. Identification of chromosomes involved in both types of change indicate that there is a non-random involvement of specific chromosomes. In addition, cytogenetic subgroups can be identified which appear to have prognostic implications. This paper reviews the results of chromosome studies in A.N.L.L.performed in thecytogenetic research unit at St St Vincent’s Hospital, from 1975 to 1978. Using short-term marrow cultures, chromosome studies were carried out on 168 patients at diagnosis; 102 were found to have abnormal karyotypes and 48 showed no chromosome abnormality. No mitoses were obtained from 18 patients. To date trypsin G-banding studies have been satisfactorily performed on 47, of whom 37 had abnormalities. The most common abnormality was trisomy 8. A specifictranslocation between 8 and 21 was identified in 3 patients and a 9;22 translocation in 2 others. All patients with acute erythroleukaemia, and the majority with A.N.L.L. occurring after long-term therapy for other haematological disorders, had abnormal karyotypes with multiple abnormalities. The response of these patients to therapy was poor, whereas those with specific translocations all achieved remission. Ten of 12 patients considered to have a preleukaemic syndrome showed chromosome abnormalities which were most frequently monosomy 7 or partial deletion of the long arms ofchromosome 5,(5q-). Similar findings have been reported in other series, but the frequency of Occurrence appears to show geographical variation. Therefore as cytogenetic patterns seem to have diagnostic, prognostic and aetiological implications in A.N.L.L., chromosome studies should always be performed at diagnosis. A PARTIAL MECHANISM FOR CENTROMERIC SUPPRESSION
Aur DANIELCytogenetrcs Unit, Prince of Wales Hospital, Randwick. New South Wales Of constderable surprise and interest to human cytogeneticists with the advent of chromosome banding, has been the number and diversity of dicentric structural rearrangements. These have been found in sex chromosomal and
ABSTRACTS OF ANNUAL MEETING
1979 141
autosomal isochromosomes, Robertsonian translocations, tandem translocations, bisatellited markets and fusion translocations. In Lima-de-Faria‘s model of the centromere, the relationship between the centromeric chromomeres and the kinetochore was unknown. On the supposition that Cd banding stains the kinetochores, a model for the centromere and centromeric suppression is proposed. FAMILIAL STUDIES ON NOR’S
DIANACHAMBERS, MALCOLM PARSLOW & MARGARET DRUMMONDDepartment of Comnzunity Health, School of Medicine, University of Auckland, New Zealand The technique of combined G-banding and silver-nitrate staining of nucleolar organizer regions (NOR’s) allows study of the presence and activity of NOR’s on specific chromosome sites. We have previously reported on the clinical and cytogenetic study of a family with a translocation t(l2;21) (pl 1;pll) where the NOR from the der (21) appears to be translocated onto the der( 12).The original analyses of the NOR’s by silver staining suggested that this site was positive in some carriers and negative in others. The activity ofthis der( 12) NOR has been further studied in repeat blood and skin fibroblast cultures to determine whether this inactivity is a ‘real’ phenomenon or due to cultural or staining differences. The results suggest that there is suppression of the der( 12) NOR in some carrier members of the family and that the satellite association of this chromosome is related to the activity of its NOR. THE EFFECTS OF m-AMSA ON LYMPHOCYTES
CAROLOLDFIELDCytogenetics Unit, Christchurch Hospital, New Zealand The antitumour drug, m-AMSA inhibits the progression of lymphocytes through the cell cycle. This is demonstrated by microdensitometry and the sister chromatid exchange technique. THE EFFECTS OF ,!I RADIATION ON SISTER CHROMATID EXCHANGES IN CULTURED HUMAN LYMPHOCYTES
PETERE. CROSSEN & WILLIAMF. MORGAN Cancer Society of’ New Zealand, Cytogenetics Unit,
Christchurch Hospital, New Zealand The incidence of Sister Chromatid Exchanges (SCE’s) due to radiation was investigated in cultured human lymphocytes using the BrdU/Giemsa technique. Cultures treated continuously with 0,001 and 0.01 pCi of 3HUridine showed no increase in either chromosome abnormalities or SCEs. Continuous treatment with 0.1pCi resulted in a significant increase in chromosome aberrations but no increase in SCE’s while treatment with 0.2 pCi gave both an increase in chromosome aberrations and SCE’s. Cultures given a 4 h pulse with 1.O pCi showed a significant increase in both SCE’s and chromosome aberrations. The results indicate that low levels of fl radiation do not cause an increase in SCEs in human lymphocytes, and that a number, ifnot all, of the exchanges observed at low levels of ,!I radiation with autoradiography, may be spontaneous events. X CHROMOSOME DELETION AND SHORT STATURE
R. L. SHAW The Princess Mary Hospitalfor Children, Auckland. New Zealand The idea that females with monosomy for the short arm of the X chromosome always have short stature was proposed in about 1960,then challenged about10 years later. It seems that little has subsequently been written about this apparent conflict. Examination of data from published cases of Xp-, Xq- and partial Xp monosomy resulting from X chromosome translocations suggests that the original hypothesis was correct, and that the critical locus is situated near-terminally on Xp. EXPERIENCE WITH FRA(X) (q27) IN RETARDED MALES AND CARRIER FEMALES
GRANTR. SUTHERLAND Cytogenetics Unit, Adelaide Children’s Hospital, South Australia The fragile site at Xq27 is associated with X-linked mental retardation with macro-orchidism. This fragile site has been studied in 21 retarded males. Chromosome studies on 11 obligate carrier females have demonstrated the site in only 3 of them. As carriers become older the fragile site becomes more difficult to demonstrate. Amongst 10 young daughters of obligate carriers, 5 have been shown to carry the fragile site. Cytogenetic carrier detection of this form of X-linked mental retardation appears to be fairly reliable in females aged less than 20-25 yr, but is unreliable after this age.