- Email: [email protected]
Diseases of DNA repair, replication and recombination
A B S T R A C T S OF A N N U A L M E E T I N G
1980
179
When reviewed at 2 y r twin one had developed normally and twin two showed the degree ofdevelopmental delaq usually associated with Down's syndrome. On the basis of placentation and blood groups these twins appear to be identical. There was an anastomotic placental vessel to explain the blood chimaericism. It is interesting to speculate on the mechanism that allowed identical twins to have different karyotypes. DISEASES OF DNA REPAIR, REPLICATION AND RECOMBINATION
PAULA IMRAY, PHII.C H E N , ROBERT RAMSAY, EEFIEGIPPS, RORrRT DAMIMN;S, P b n x UIY'ROFI'& CHCVK IDSON Quumsland Insiiiuie of Mm.lical Rrsuarch I t is estimated that approximately I00 gene loci are involved in coding for functions concerned with the processing of DNA, such a s replication, repair and recombination. Diseases associated with mutations i n this gene cliish include the autosomal recessive disorders xeroderma pigmentosum, ataxia telangiectasia, Cockayne's syndrome, Bloom's syndrome. Rothmund-Thompson syndrome and Fanconi's anaemia. Other disorders in this group, inherited as dominant traits, include some forms of retinoblastoma (D-deletion), Gardiner's syndrome. fainiliiil melanoma and some 'cancer-prone' families. Recently evidence has accrued which suggests there is ii high correlation between ionizing radiosensitivity and Huntington's disease, while this may also be true of some other types of dementia including a proportion of cases of Alzheimer's disease. Some selective developmental anomnlie\ of the immune system may also be related to mutants of this general class. Emph to date has been on ihc sensitivity of these mutants to extrinsically generated DNA damage. There is reason, however, to believe that some o f the pleotropic effects observed clinically in those with an early onset of symptoms are due to developmental anomalies related to abnormal DNA replication or recombination events in embryo. Where ncuronal loss occurs at a much later age, both programmed degeneration and accumulation of damage must be considered. FRAGILE SITES ON HUMAN CHROMOSOMES
G R A N T R. SUTHERLAND Cytogenetics Unit, The Adelaidc~C'liildwn '.\ tlos,vitcrl Fragilc sites have been documented at 2ql1, 10q23, 10q25, 1 lq23, 16q12, 16q22, 20pl I and Xq27. These arc hei-itable chromosome markers which can be demonstrated in lymphocyte cultui-c. Special culture mcdium IS required for all except the one at 16q22: it iiiuSt be free offolic acid and thymidine to demonstrate all the others with the exception of the site at 10q25 which requires the presence of BrdU. The autosomal sites are without apparent phenotypic effect in the heterozygote but homozygotes have not been documented. The BrdU requiring site IS present i n about 1 in 35 of the South Australian population. hence if homozygotes are viable about 4 per yr would be born in the State. The fragile site at Xq27 produces a mental retardation syndromc. which is the commonest chromosonially determined cause of mental retardation after Down's syndrome. From the South Australian population ol' approximately 1.2 million. 25 such males have been identified and the fra(X)(q27)chromosome has been shown 10 be segregating in 9 Ihmilies, most of which are of Anglo-Saxon origin. Difficulties have been encountered in deinoiistrciting this fragile site, especially in females and skin fibroblasts. GALT PHENOTYPING WITH GALACTOSAEMIA SCREENING
JOHN C. MULLEY*, EVELYN R~BERTXIN-I & A. C. W I L K I N S *C,p/ogcwriic~,c ~ Uuit, Dc,pcrrirmwt O/ Hi.ytopathology. The AdcJlaide Children '.F Hospital and tDc~prrrimcwrof Chcniic~alPtrtholo,qj., The Adelaidc~Children '.F Hospital Galactosaemia is an autosomal recessive disorder arising from deficiency of the enzyme galactose-l -phosphate uridyl transferase (GALT). Enzyme activities determined by the 3 alleles, N, D and *G', are IOO",,, 50':,, and approximately O",,, respectively. Expected activity levels for the genotypes ND, DD, NG and D G are 75",,, SO",,, 50?6 and 25% respectively. Alleles N and D are eleetroplioi-etically distinguishable and corresponding nllele frequencies from 69 Adelaide newborns are .92 and .08. In the absence of phenotyping, confusion may arise in the interpretation of quantitative results when both D and G segregate within a Family. New born propositi are routinely detected by mass screening on the basis oflow GALT activity from bloodspots. Subsequently. those tests found deficient on screen have activity quantitated, and are phenotyped by electrophoresls of haemolysates. Where activity is low, detection of a D band in the propositus differentiates the classical (GG) galactosaemic infant from the DG variant type with 25% normal activity. Phenotypic studies of parents confirms this.
1980
179
When reviewed at 2 y r twin one had developed normally and twin two showed the degree ofdevelopmental delaq usually associated with Down's syndrome. On the basis of placentation and blood groups these twins appear to be identical. There was an anastomotic placental vessel to explain the blood chimaericism. It is interesting to speculate on the mechanism that allowed identical twins to have different karyotypes. DISEASES OF DNA REPAIR, REPLICATION AND RECOMBINATION
PAULA IMRAY, PHII.C H E N , ROBERT RAMSAY, EEFIEGIPPS, RORrRT DAMIMN;S, P b n x UIY'ROFI'& CHCVK IDSON Quumsland Insiiiuie of Mm.lical Rrsuarch I t is estimated that approximately I00 gene loci are involved in coding for functions concerned with the processing of DNA, such a s replication, repair and recombination. Diseases associated with mutations i n this gene cliish include the autosomal recessive disorders xeroderma pigmentosum, ataxia telangiectasia, Cockayne's syndrome, Bloom's syndrome. Rothmund-Thompson syndrome and Fanconi's anaemia. Other disorders in this group, inherited as dominant traits, include some forms of retinoblastoma (D-deletion), Gardiner's syndrome. fainiliiil melanoma and some 'cancer-prone' families. Recently evidence has accrued which suggests there is ii high correlation between ionizing radiosensitivity and Huntington's disease, while this may also be true of some other types of dementia including a proportion of cases of Alzheimer's disease. Some selective developmental anomnlie\ of the immune system may also be related to mutants of this general class. Emph to date has been on ihc sensitivity of these mutants to extrinsically generated DNA damage. There is reason, however, to believe that some o f the pleotropic effects observed clinically in those with an early onset of symptoms are due to developmental anomalies related to abnormal DNA replication or recombination events in embryo. Where ncuronal loss occurs at a much later age, both programmed degeneration and accumulation of damage must be considered. FRAGILE SITES ON HUMAN CHROMOSOMES
G R A N T R. SUTHERLAND Cytogenetics Unit, The Adelaidc~C'liildwn '.\ tlos,vitcrl Fragilc sites have been documented at 2ql1, 10q23, 10q25, 1 lq23, 16q12, 16q22, 20pl I and Xq27. These arc hei-itable chromosome markers which can be demonstrated in lymphocyte cultui-c. Special culture mcdium IS required for all except the one at 16q22: it iiiuSt be free offolic acid and thymidine to demonstrate all the others with the exception of the site at 10q25 which requires the presence of BrdU. The autosomal sites are without apparent phenotypic effect in the heterozygote but homozygotes have not been documented. The BrdU requiring site IS present i n about 1 in 35 of the South Australian population. hence if homozygotes are viable about 4 per yr would be born in the State. The fragile site at Xq27 produces a mental retardation syndromc. which is the commonest chromosonially determined cause of mental retardation after Down's syndrome. From the South Australian population ol' approximately 1.2 million. 25 such males have been identified and the fra(X)(q27)chromosome has been shown 10 be segregating in 9 Ihmilies, most of which are of Anglo-Saxon origin. Difficulties have been encountered in deinoiistrciting this fragile site, especially in females and skin fibroblasts. GALT PHENOTYPING WITH GALACTOSAEMIA SCREENING
JOHN C. MULLEY*, EVELYN R~BERTXIN-I & A. C. W I L K I N S *C,p/ogcwriic~,c ~ Uuit, Dc,pcrrirmwt O/ Hi.ytopathology. The AdcJlaide Children '.F Hospital and tDc~prrrimcwrof Chcniic~alPtrtholo,qj., The Adelaidc~Children '.F Hospital Galactosaemia is an autosomal recessive disorder arising from deficiency of the enzyme galactose-l -phosphate uridyl transferase (GALT). Enzyme activities determined by the 3 alleles, N, D and *G', are IOO",,, 50':,, and approximately O",,, respectively. Expected activity levels for the genotypes ND, DD, NG and D G are 75",,, SO",,, 50?6 and 25% respectively. Alleles N and D are eleetroplioi-etically distinguishable and corresponding nllele frequencies from 69 Adelaide newborns are .92 and .08. In the absence of phenotyping, confusion may arise in the interpretation of quantitative results when both D and G segregate within a Family. New born propositi are routinely detected by mass screening on the basis oflow GALT activity from bloodspots. Subsequently. those tests found deficient on screen have activity quantitated, and are phenotyped by electrophoresls of haemolysates. Where activity is low, detection of a D band in the propositus differentiates the classical (GG) galactosaemic infant from the DG variant type with 25% normal activity. Phenotypic studies of parents confirms this.