Exclusive paternal origin of new mutations in Apert syndrome

Moloney, Dominique M.; Slaney, Sarah R; Oldridge, Michael; Wall, Steven A.; Sahlin, Pelle; Stenman, Göran; Wilkie, Andrew O.M.

doi:10.1038/ng0596-48

Cited by 279 publications

(183 citation statements)

References 42 publications

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“…The list of diseases in which the parental origin of new mutations was elucidated through the use of molecular analysis is listed in Table 3. Exclusive paternal origin of new mutations with a paternal age effect was found for mutations in the FGFR2 (Apert, Crouzon and Pfeiffer syndromes), 14,15 FGFR3 (achondroplasia), 16 and RET (MEN 2A and MEN 2B) 17,18 genes. Until recently, the most favored explanation for these observations was that the mutations arise during cell replication, and the predominance of new mutations in the male germ line is due to the increased number of germ line cell divisions in spermatogenesis compared with that in oogenesis.…”

Section: Discussionmentioning

confidence: 99%

Parental origin of mutations in sporadic cases of Treacher Collins syndrome

et al. 2003

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In some autosomal dominant conditions, there is a correlation between new mutations and paternal age, with new mutations arising almost exclusively in the male germ line. To test this hypothesis in Treacher Collins syndrome, we analyzed 22 sporadic cases, determining the parental origin of the pathogenic mutation in 10 informative families. Mutations were found to be of both paternal and maternal origin, without a detectable parental age effect, confirming that a paternal age effect is not universal to all autosomal dominant disorders. A discussion on the parental origin of mutations and paternal age effect in other diseases is included.

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Section: Discussionmentioning

confidence: 99%

Parental origin of mutations in sporadic cases of Treacher Collins syndrome

et al. 2003

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“…9,10 Sporadic cases of AS, CS and PS have been associated with advanced paternal age and the origin of FGFR2 mutations in these three conditions was demonstrated to be exclusively paternal. 11,12 Surprisingly, the same FGFR2 mutation can give rise to CS, PS or JW phenotype. 6,13 Until 2002, FGFR2 mutations had been identified almost exclusively in the extracellular domain of the receptor mainly in exons 8 (IIIa) and 10 (IIIc) encoding the third immunoglobulin-like (Ig III) loop and appeared to account for only 50% of CS and PS cases.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

et al. 2006

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Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

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“…Notable examples of a nearly exclusive paternal origin are provided by dominant pathological mutations in three genes, FGFR2 (causing Apert, Crouzon, and Pfeiffer syndromes), FGFR3 (causing achondroplasia and related bone dysplasias), and RET (causing multiple endocrine neoplasia type 2), all of which encode members of the receptor tyrosine kinase family (5)(6)(7)(8)(9)(10)(11). In addition, the average age of the fathers originating these mutations is elevated by 2-5 years (12,13).…”

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confidence: 99%

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Goriely

McVean²,

Pelt³

et al. 2005

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

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133

109

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Despite the importance of mutation in genetics, there are virtually no experimental data on the occurrence of specific nucleotide substitutions in human gametes. C>G transversions at position 755 of FGF receptor 2 (FGFR2) cause Apert syndrome; this mutation, encoding the gain-of-function substitution Ser252Trp, occurs with a birth rate elevated 200-to 800-fold above background and originates exclusively from the unaffected father. We previously demonstrated high levels of both 755C>G and 755C>T FGFR2 mutations in human sperm and proposed that these particular mutations are enriched because the encoded proteins confer a selective advantage to spermatogonial cells. Here, we examine three corollaries of this hypothesis. First, we show that mutation levels at the adjacent FGFR2 nucleotides 752-754 are low, excluding any general increase in local mutation rate. Second, we present three instances of double-nucleotide changes involving 755C, expected to be extremely rare as chance events. Two of these double-nucleotide substitutions are shown, either by assessment of the pedigree or by direct analysis of sperm, to have arisen in sequential steps; the third (encoding Ser252Tyr) was predicted from structural considerations. Finally, we demonstrate that both major alternative spliceforms of FGFR2 (Fgfr2b and Fgfr2c) are expressed in rat spermatogonial stem cell lines. Taken together, these observations show that specific FGFR2 mutations attain high levels in sperm because they encode proteins with gain-of-function properties, favoring clonal expansion of mutant spermatogonial cells. Among FGFR2 mutations, those causing Apert syndrome may be especially prevalent because they enhance signaling by FGF ligands specific for each of the major expressed isoforms.Apert syndrome ͉ FGF receptor 2 ͉ paternal age ͉ selfish mutation

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Exclusive paternal origin of new mutations in Apert syndrome

Cited by 279 publications

References 42 publications

Parental origin of mutations in sporadic cases of Treacher Collins syndrome

Parental origin of mutations in sporadic cases of Treacher Collins syndrome

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

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