| 1. |
- Bjursell, Cecilia, 1971
(författare)
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Genetics of the carbohydrate-deficient glycoprotein syndrome type Ia
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, a revolution in the development of new techniques have made it possible to perform genetic studies of inherited disorders without prior knowledge about the gene product or the function of the gene. The techniques include linkage studies, allelic association studies, physical mapping and the sequencing of candidate genes for finding disease causing mutations. This thesis describes one such case; genetic linkage studies led to the characterization of a chromosomal location and together with studies from other laboratories, to the identification and detailed characterization of the disease gene involved. About 20 years ago, the carbohydrate-deficient glycoprotein (CDG) syndrome was first discovered in a monozygous twin pair. Within a few years several children were diagnosed to have the same syndrome based on clinical and biochemical analysis. The CDG syndrome type Ia has an early neonatal presentation and all children develop cerebellar atrophy, mental retardation and a psychomotor delay. The biochemical characteristics of the syndrome are complex defects in the carbohydrate residues of many serum glycoproteins. In Sweden approximately one child in 70,000 is born with the CDG syndrome and 30% of these children die before the age of five.The overall aim of this study was to find the genetic alteration which causes the CDG syndrome type Ia and to understand the biochemical changes that characterize the syndrome. The study started in 1993 with 25 CDG type Ia patients. In the first paper (published in 1994) we could, for the first time, map the gene to chromosome 16p13 (CDG1 gene region). Significant linkage disequilibrium could also be demonstrated for one of the polymorphic markers located in the CDG1 gene region. The next paper (1997) presented the fine mapping of this region. We could in this paper delimit the region from 13cM to less than 1cM and less than 1Mb based on the specific haplotype found mainly in Scandinavian families. This was a region small enough for physical mapping. In the third paper (1998) we could present data on fine mapping of the PMM2 gene and on a mutation in the PMM2 gene that correlated to the specific Scandinavian haplotype. An evaluation was also done of 15 prenatal diagnostic cases. The last paper (2000) presents the complete PMM2 gene mutation spectrum of the CDG type Ia patients in our study. Most of the mutations were found in exon 5 (61%) and exon 8. A conclusion drawn from this is that exon 5 should be screened first in prenatal diagnostic cases.Specific genetic alterations can open up new possibilities for better diagnostic tools of both carrier and prenatal situations and hence help such families. Furthermore this study can result in a better understanding of the glycosylation pathway and in the future be of help for understanding the genetic explanation of other CDG variants. Finally the information obtained in this study can comprise the basis for the development of adequate therapy.
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| 2. |
- Bjursell, Cecilia, 1971, et al.
(författare)
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PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families.
- 2000
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Ingår i: Human mutation. - 1098-1004 .- 1059-7794. ; 16:5, s. 395-400
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Tidskriftsartikel (refereegranskat)abstract
- Carbohydrate-deficient glycoprotein syndrome type IA (CDG IA) is an autosomal recessive disease characterized clinically by severe involvement of the central and peripheral nervous system, and biochemically by complex defects in carbohydrate residues in a number of serum glycoproteins. CDG IA is caused by mutations in the PMM2 gene located in chromosome region 16p13. In this study, 61 CDG type IA patients (122 chromosomes) were screened for mutations in the PMM2 gene using a combination of SSCP and sequence analysis. More than 95% of the mutations could be detected. All of them were missense mutations. Mutations 422G>A and 357C>A were strikingly more common in the material and comprised 58% of mutations detected. Of the 20 mutations found, 10 were not reported previously. Seven mutations, e.g. 26G>A (five alleles) and 548T>C (seven alleles), were found only in Scandinavian families. The most common genotype was 357C>A/422G>A (36%). Three patients were homozygous, 357C>A/357C>A (two cases), and 548T>C/548T>C (one case). No patients homozygous for the most common mutation 422G>A were detected. The different mutations were clustered e.g., in that most were located in exon 5 (five) and exon 8 (six), while no mutation was detected in exon 2. When the frequencies of each mutation were included, exon 5 comprised 61% (65 chromosomes) of the mutations; in Scandinavian patients the frequency of these mutations was 72%. Thus, analysis of exon five in these patients enables both reliable and time-saving first screening in prenatal diagnostic cases. This could be followed by a second step of additional strategies for the detection of other mutations.
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| 3. |
- Einbeigi, Zakaria, 1962, et al.
(författare)
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Occurrence of both breast and ovarian cancer in a woman is a marker for the BRCA gene mutations: a population-based study from western Sweden.
- 2007
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Ingår i: Familial cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 6:1, s. 35-41
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Tidskriftsartikel (refereegranskat)abstract
- AIM: This study aimed to analyze whether the occurrence of both breast and ovarian cancer in a woman serves as a marker for BRCA gene mutations. MATERIAL AND METHODS: This population-based study included 256 women in western Sweden who developed both invasive breast and ovarian tumors between 1958 and 1999. Archival paraffin tissue blocks of their tumors were retrieved for DNA-extraction to analyze the founder mutation, BRCA1 c.3171_3175dup (c.3171ins5), which is most common in this geographic area and four other common Scandinavian BRCA1 gene mutations and one BRCA2 mutation. Together, account these mutations for approximately 75% of the BRCA1/2 gene mutations in the clinical unit. RESULTS: Ninteen percent (95% confidence interval (CI) 14-24%) of the women carried one of the analyzed BRCA1 gene mutations but none of the women were positive for the analyzed BRCA2 mutation. One-third of the women with both tumors before age 60 were mutation carriers. BRCA1 c.3171_3175dup (c.3171ins5) constituted 84% of all identified mutations. Although the majority of breast cancers were invasive ductal and atypical medullary types, a variety of other breast malignancies were seen among mutation carriers. Serous ovarian carcinomas predominated among ovarian tumors. A variety of other ovarian tumors, including three granulosa-theca cell tumors, were also observed among mutation carriers. CONCLUSIONS: The occurrence of both breast and ovarian cancer in a woman is associated with a high likelihood of a constitutional BRCA1 mutation. These women and their families might therefore be considered for mutation screening after appropriate genetic counselling.
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