Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis

Rannan-Eliya, Sahan V.; Taylor, Indira B.; Heer, Inge Marieke de; Ouweland, Ans M.W. van den; Wall, Steven A.; Wilkie, Andrew O.M.

doi:10.1007/s00439-004-1151-5

Cited by 73 publications

(42 citation statements)

References 34 publications

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“…Supporting this hypothesis are the findings in Apert syndrome, achondroplasia and Muenke syndrome, due to missense mutations in FGFR2 and FGFR3, respectively, with exclusive paternal origin of new mutations resulting in constitutive activation or increased ligand binding of the protein product [Moloney et al, 1996;Rannan-Eliya et al, 2004]. The paternal age effect observed in Costello syndrome [Lurie, 1994], in combination with …”

Section: Discussionmentioning

confidence: 57%

HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

Gripp

Lin

Stabley

et al. 2005

American J of Med Genetics Pt A

175

187

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Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

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Section: Discussionmentioning

confidence: 57%

HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

Gripp

Lin

Stabley

et al. 2005

American J of Med Genetics Pt A

175

187

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“…Heterozygous missense mutations causing constitutive activation of the protein product often occur in the paternal germline, as suggested by Penrose [1955] who proposed that mitotic replication errors accumulate in male germ cells. Supporting this hypothesis are the findings in Apert syndrome, achondroplasia and Muenke syndrome, due to missense mutations in FGFR2 and FGFR3, respectively, with exclusive paternal origin of new mutations resulting in constitutive activation or increased ligand binding of the protein product [Moloney et al, 1996;Rannan-Eliya et al, 2004]. The paternal age effect observed in Costello syndrome [Lurie, 1994] suggests a paternal origin of the mutations and led us to investigate the origin of mutations in CS.…”

Section: Introductionmentioning

confidence: 70%

Paternal bias in parental origin ofHRASmutations in Costello syndrome

Sol‐Church¹,

Stabley²,

Nicholson³

et al. 2006

Hum. Mutat.

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Costello syndrome (CS) is a rare congenital condition caused by heterozygous de novo missense mutations affecting the codon for glycine 12 or 13 of the HRAS gene. We have identified 39 CS patients harboring the p.Gly12Ser mutation (NM_005343.2:c.34 G > A), two patients with c.35G > C mutations resulting in p.Gly12Ala substitutions, and one patient carrying the p.Gly13Cys substitution (c.37G > A). We analyzed the region flanking the mutated sites in 42 probands and 59 parents, and used four polymorphic markers to trace the parental origin of the germline mutations: one highly polymorphic hexanucleotide (GGGCCT) repeat region, defining three alleles with different numbers of repeat units (two, three, or four), and three SNPs. One of the SNPs, rs12628 (c.81T > C), was found in strong linkage disequilibrium with the hexanucleotide repeat region. Out of a total of 24 probands with polymorphic markers, 16 informative families were tested and the paternal origin of the germline mutation was found in 14 CS probands; a distribution that is neither consistent with an equal likelihood of mutations arising in either parent (P = 0.0018), nor with exclusive paternal origin.

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“…The AGES group was predominantly white, and the JHMI group had more individuals of African-American and Asian-Pacific descent, suggesting sociodemographic explanations for the disparity in results. In addition to ACH and AS, there are Ϸ20 autosomal dominant genes with significant paternal-age components and strong evidence of paternal origin of mutation including Crouzon, Pfeiffer, MEN 2A, MEN 2B, progeria, and familial adenomatous polyposis (9,(55)(56)(57). Comparative studies of the underlying mutations in sperm may help us to better understand the mechanisms of age effects across loci, selection during spermatogenesis, genetic variation within loci, and group-specific differences.…”

Section: Ach and Asmentioning

confidence: 99%

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

Wyrobek

Eskenazi

Young

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

366

206

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This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < 0.01) with no evidence for age thresholds. However, we found no associations between age and the frequencies of sperm with immature chromatin, aneuploidies͞diploidies, FGFR2 mutations (Apert syndrome), or sex ratio in this cohort. There were also no consistent correlations among genomic and semen-quality endpoints, except between DFI and sperm motility (r ‫؍‬ ؊0.65, P < 0.001). These findings suggest there are multiple spermatogenic targets for genomically defective sperm with substantially variable susceptibilities to age. Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring (Down, Klinefelter, Turner, triple X, and XYY syndromes) or triploid embryos. Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.DNA fragmentation ͉ human sperm ͉ achondroplasia ͉ sperm FISH ͉ Apert syndrome I t has become more socially acceptable to delay fatherhood, but the heritable consequences of this trend remain poorly understood. Since 1980, U.S. birth rates have increased up to 40% for men 35-49 years and have decreased up to 20% for men under 30 (1). Although it is well known that as women age, they are at increased risk for infertility, spontaneous abortion, and genetic and chromosomal defects among offspring, the association of male aging with these outcomes has been less well characterized (2).Advancing paternal age has been implicated in a broad range of abnormal reproductive and genetic outcomes (3, 4), including diminished semen quality (5), reduced fertility (6), increased frequencies of spontaneous abortions (7, 8), Ϸ20 autosomal dominant diseases including achondroplasia (ACH) and Apert syndrome (AS; see refs. 3 and 9), and several diseases of complex etiology such as schizophrenia (10). Among transmitted chromosomal defects, sex-chromosomal aneuploidy syndromes show substantial paternal contributions with some evidence of paternal-age effects (11-13).However, the mechanisms for age dependency of paternally transmitted genomic defects are ...

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Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis

Cited by 73 publications

References 34 publications

HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

Paternal bias in parental origin ofHRASmutations in Costello syndrome

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

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