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- Beleza-Meireles, Ana, et al.
(författare)
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Complex aetiology of an apparently Mendelian form of mental retardation
- 2008
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated. METHODS: After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree. RESULTS: No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status. CONCLUSION: These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons may underlie the phenotypic variation of intelligence and explain instances of intellectual impairment.
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| 2. |
- Beleza Meireles, Ana Maria
(författare)
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Hypospadias : analysis of a complex genetic disorder
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Hypospadias is a common inborn error of the male urethra that involves an abnormally placed urethral opening. Its complex etiology is largely elusive to date. Twin and familial studies highlight a genetic background in hypospadias. Environmental factors have also been identified, particularly the exposure to endocrine disrupters. For most of the cases, pedigree analyses indicate a heterogeneous, complex pattern of inheritance, with several genetic and environmental factors interacting, yielding high heritability indices. Hypospadias is therefore said to be a complex genetic disorder. HYPOTHESIS: As an inborn error of development, hypospadias may be induced by disturbances in the pathways of urethral development, which comprise genetic programming, cell differentiation, hormonal signaling, enzyme activity, and tissue remodeling; and follows an orderly sequence. We proposed that gene variants in FGF8, FGF10, FGFR2 and BMP7, important genes in the early urethral development; in FKBP52, an androgen receptor cochaperone; in the estrogen receptor (ESR) genes 1 and 2; and ATF3, an estrogen responsive gene; may influence the risk to hypospadias. STRATEGY: Using a candidate gene strategy, we performed comprehensive analysis of these genes in DNA from boys with hypospadias and controls, including sequence analysis, genotyping and association studies; and complementary expression analysis in human tissues. RESULTS: Our results indicate that gene variants in the sequence of FGF8, FGFR2, two androgen‐regulated developmental genes; and of ESR2 and ATF3, two estrogen related genes, are associated with hypospadias. We have shown that the last is expressed in the human developing male urethra. DISCUSSION: The molecular mechanisms involved in the development of external genitalia during fetal life seem to depend on a complex balance between early morphogenetic cell‐cell interactions; and between sex steroid hormones. These balances can be disturbed by the exposure to environmental endocrine disruptors. Ethnical differences in the response to such exposures denote that genetic factors also play an important role. The involvement of sequence variants in FGFR2, FGF8, ESR2 and ATF3, hormonal responsive genes, in hypospadias is reported in this thesis, increasing the understanding on the complex etiology of hypospadias. Further genetic analysis and gene‐environment studies are encouraged.
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