Hypospadias : analysis of a complex genetic disorder
Author: Beleza Meireles, Ana Maria
Date: 2007-08-31
Location: Rolf Lufts auditorium, L1, Karolinska Universitetssjukhuset, Stockholm
Time: 9.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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thesis.pdf (2.257Mb)
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.
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.
List of papers:
I. Beleza-Meireles A, Lundberg F, Lagerstedt K, Zhou X, Omrani D, Frisén L, Nordenskjöld A (2007). "FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias." Eur J Hum Genet 15(4): 405-10. Epub 2007 Jan 31
Pubmed
II. Beleza-Meireles A, Barbaro M, Wedell A, Töhönen V, Nordenskjöld A (2007). "Studies of a co-chaperone of the androgen receptor, FKBP52, as candidate for hypospadias." Reprod Biol Endocrinol 5: 8
Pubmed
III. Beleza-Meireles A, Omrani D, Kockum I, Frisén L, Lagerstedt K, Nordenskjöld A (2006). "Polymorphisms of estrogen receptor beta gene are associated with hypospadias." J Endocrinol Invest 29(1): 5-10
Pubmed
IV. Beleza-Meireles A, Kockum I, Lundberg F, Söderhäll C, Nordenskjöld A (2007). "Risk factors for hypospadias in the estrogen receptor 2 gene." J Clin Endocrinol Metab Jun 19: Epub ahead of print
Pubmed
V. Beleza-Meireles A, Töhönen V, Radmayr C, Schwentner C, Soderhall C, Kockum I, Nordenskjold A (2007). "Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias." (Submitted)
I. Beleza-Meireles A, Lundberg F, Lagerstedt K, Zhou X, Omrani D, Frisén L, Nordenskjöld A (2007). "FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias." Eur J Hum Genet 15(4): 405-10. Epub 2007 Jan 31
Pubmed
II. Beleza-Meireles A, Barbaro M, Wedell A, Töhönen V, Nordenskjöld A (2007). "Studies of a co-chaperone of the androgen receptor, FKBP52, as candidate for hypospadias." Reprod Biol Endocrinol 5: 8
Pubmed
III. Beleza-Meireles A, Omrani D, Kockum I, Frisén L, Lagerstedt K, Nordenskjöld A (2006). "Polymorphisms of estrogen receptor beta gene are associated with hypospadias." J Endocrinol Invest 29(1): 5-10
Pubmed
IV. Beleza-Meireles A, Kockum I, Lundberg F, Söderhäll C, Nordenskjöld A (2007). "Risk factors for hypospadias in the estrogen receptor 2 gene." J Clin Endocrinol Metab Jun 19: Epub ahead of print
Pubmed
V. Beleza-Meireles A, Töhönen V, Radmayr C, Schwentner C, Soderhall C, Kockum I, Nordenskjold A (2007). "Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias." (Submitted)
Issue date: 2007-08-10
Rights:
Publication year: 2007
ISBN: 978-91-7357-249-1
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