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- Hellerud, Christina, 1955, et al.
(author)
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Clinical heterogeneity and molecular findings in five Polish patients with glycerol kinase deficiency: investigation of two splice site mutations with computerized splice junction analysis and Xp21 gene-specific mRNA analysis.
- 2003
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In: Molecular genetics and metabolism. - 1096-7192. ; 79:3, s. 149-59
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Journal article (peer-reviewed)abstract
- Five cases of glycerol kinase deficiency are presented with clinical, biochemical, and genetic results. Two had the glycerol kinase deficiency as part of an Xp21 contiguous gene deletion syndrome-complex form-and three had an isolated form of the enzyme deficiency. In these we found two splice site mutations (IVS1+4A>G, IVS9-1G>T) and one insertion (1393_1394insG). In patients with the complex form, a deletion of the DAX1, GK genes and the distal part of the DMD gene was found. A computerized study was performed to predict the effects of the splice site mutations. It showed that the IVS9-1G>T mutation substantially altered and removed the wild-type site and enhanced a cryptic site seven nucleotides downstream, and that the IVS1+4A>G diminished the strength of the wild-type donor site from strong to leaky. To verify these predictions, we developed an RT-PCR system with gene-specific primers that exclusively amplifies the Xp21 glycerol kinase gene transcript. Identification of individuals at risk is motivated by a need to avoid delay in a correct diagnosis. For reliable identification of heterozygotes for isolated glycerol kinase deficiency, knowledge of the specific mutation in the proband is required. This is easily obtained with the RT-PCR analyses developed in this study.
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2. |
- Jernström, Helena, et al.
(author)
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Genetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk
- 2001
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In: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 72:2, s. 144-154
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Journal article (peer-reviewed)abstract
- The oral contraceptive pill is associated with a modest increase in the risk of early-onset breast cancer in the general population, but it is possible that the risk is higher in certain subgroups of women. The relative risk of breast cancer associated with oral contraceptive use has been reported to be higher for African-American women than for white women. African-American women also have a higher incidence of premenopausal breast cancer than white women. Circulating levels of insulin-like growth factor-1 (IGF-I) vary between ethnic groups and are positively associated with the risk of premenopausal breast cancer. In general, the plasma level of IGF-I is lower in women who take oral contraceptives than in women who do not. In an attempt to explain the observed ethnic difference in IGF-I levels with oral contraceptive use, we sought to identify polymorphic variants of genes that are associated with IGF-I levels and estrogen metabolism. We measured IGF-I and IGFBP-3 plasma levels in 503 nulligravid women between the ages of 17 and 35. All women filled out a questionnaire that included information about ethnic background and oral contraceptive use. Samples of DNA were used to genotype the women for known polymorphic variants in the IGF1, AIB1, and CYP3A4 genes. Black women had significantly higher mean IGF-I levels than white women (330 ng/ml versus 284 ng/ml; P = 0.001, adjusted for age and oral contraceptive use). IGF-I levels were significantly suppressed by oral contraceptives in white women (301 ng/ml versus 267 ng/ml; P = 0.0003), but not in black women. Among oral contraceptive users, the IGF-I level was positively associated with the absence of the IGF1 19-repeat allele (338 ng/ml versus 265 ng/ml; P = 0.00007), with the presence of the CYP3A4 variant allele (320 ng/ml versus 269 ng/ml; P = 0.01), and with the presence of the AIB1 26-repeat allele (291 ng/ml versus 271; P = 0.08). After adjusting for genotypes, ethnic group was no longer a significant predictor of the IGF-I level. IGF-I levels are higher among black than white women. Polymorphic variants in the CYP3A4, IGF1, and AIB1 genes are associated with increases in the plasma levels of IGF-I among oral contraceptive users and the variant alleles are much more common in black women than in white women. The high incidence of premenopausal breast cancer among black women may be mediated through genetic modifiers of circulating levels of IGF-I.
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4. |
- Lai, Joe, et al.
(author)
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CYP gene polymorphisms and early menarche
- 2001
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In: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 74:4, s. 449-457
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Journal article (peer-reviewed)abstract
- Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-three nulliparous women between ages 17 and 35, of various ethnic backgrounds, completed a questionnaire that included information about menstrual history. Samples of DNA were provided and used to genotype these women for polymorphic variants in the four genes. There was no significant difference in mean age at menarche between women who carried two variant CYP17 A2 alleles (12.5 years) and women who carried one or no variant allele (12.5 years) (P = 0.8, adjusted for ethnic group and year of birth). Similar results were found for the CYP1B1*3 variant allele and for the CYP1A2*1F variant allele. Women who carried two variant CYP3A4*1B alleles had an earlier mean age at menarche (12.0 years) than women who carried one or no variant allele (12.6 years) (P = 0.02). However, after adjusting for ethnic group and year of birth, no significant differences in mean age at menarche were found. The polymorphic variants of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes are unlikely to influence age of menarche.
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