Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case

Schaefer, Frederick V.; Anderson, Christine B.; Can, Billur; Say, Burhan

doi:10.1002/(sici)1096-8628(19980123)75:3<252::aid-ajmg4>3.0.co;2-s

Cited by 71 publications

(50 citation statements)

References 7 publications

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“…6 Mutations in the FGFR 2 gene have been previously linked to Pfeiffer syndrome. 10,11 Fibroblast growth factors (FGFs) are heparin-binding polypeptides which bind to FGF receptors (FGFR). 10 Once activated, intracellular signaling contributes to cellular development, differentiation, migration, angiogenesis and wound healing.…”

Section: Discussionmentioning

confidence: 99%

A case report of a patient with Pfeiffer syndrome, an FGRF 2 mutation (Trp290Cys) and unique ocular anterior segment findings

Barry

Zackai

et al. 2010

Ophthalmic Genetics

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Section: Discussionmentioning

confidence: 99%

A case report of a patient with Pfeiffer syndrome, an FGRF 2 mutation (Trp290Cys) and unique ocular anterior segment findings

Barry

Zackai

et al. 2010

Ophthalmic Genetics

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“…In addition, the Trp290Cys mutation predicts the formation of an unpaired Cys that can participate in intermolecular receptor dimerization. Both types of codon changes have been previously described in PS (Tartaglia et al 1997;Schaefer et al 1998). …”

Section: Known Missense Mutationsmentioning

confidence: 98%

Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome

Cornejo-Roldan

Roessler

Muenke³

1999

Human Genetics

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Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes correlated with specific mutations in the human fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2. In this study, we set out to examine the exons in FGFR2 most commonly associated with mutations in PS, exons IIIa and IIIc, in a panel of 78 unrelated individuals with PS by the most sensitive method (direct DNA sequencing). We have identified a total of 18 different mutations among 40 patients; eight of these mutations have not been previously described. The mutational spectrum displays a non-random character with the frequent involvement of cysteine codons.

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“…2B), in the five testes for which additional immunopositive tubules were present in the same FFPE section, at least one of these tubules did not carry the original mutation. We selected three such tubular clusters for a further round of HaloPlex sequencing using the same triplicate strategy and identified a mutation different from that present in the original immunopositive tubule in every case; the mutations (Table 1) were FGFR2 c.870G>T (p.W290C; Pfeiffer syndrome) (19) in testis 16-D (Fig. 2B), and PTPN11 c.215C>T [p.A72V; oncogenic (36), no germline cases reported] in testes 8-E and 13-G (Fig.…”

Section: Proof-of-principle Study To Identify Mutations In Immunoposimentioning

confidence: 99%

“…Fertilization of the egg by a mutant sperm leads to serious congenital disorders in the next generation, characterized by multiple malformations and, in some cases, a predisposition to malignancy. These disorders include Apert, Crouzon, and Pfeiffer syndromes [caused by FGF receptor 2 (FGFR2) mutations] (17)(18)(19)(20), achondroplasia and thanatophoric dysplasia (TD) [FGF receptor 3 (FGFR3)] (21-23), multiple endocrine neoplasia (RET) (24), Noonan syndrome [protein tyrosine phosphatase, non-receptor type 11 (PTPN11)] (25), and Costello syndrome [Harvey rat sarcoma viral oncogene homolog (HRAS)] (25). Consistent with the proposed clonal expansion mechanism, strong gain-offunction mutations of HRAS and FGFR3 have been identified in spermatocytic tumor (seminoma), a testicular tumor characteristically occurring in older men (16,26).…”

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confidence: 99%

Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes

Maher

McGowan

Giannoulatou

et al. 2016

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

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De novo point mutations arise predominantly in the male germline and increase in frequency with age, but it has not previously been possible to locate specific, identifiable mutations directly within the seminiferous tubules of human testes. Using microdissection of tubules exhibiting altered expression of the spermatogonial markers MAGEA4, FGFR3, and phospho-AKT, whole genome amplification, and DNA sequencing, we establish an in situ strategy for discovery and analysis of pathogenic de novo mutations. In 14 testes from men aged 39-90 y, we identified 11 distinct gain-of-function mutations in five genes (fibroblast growth factor receptors FGFR2 and FGFR3, tyrosine phosphatase PTPN11, and RAS oncogene homologs HRAS and KRAS) from 16 of 22 tubules analyzed; all mutations have known associations with severe diseases, ranging from congenital or perinatal lethal disorders to somatically acquired cancers. These results support proposed selfish selection of spermatogonial mutations affecting growth factor receptor-RAS signaling, highlight its prevalence in older men, and enable direct visualization of the microscopic anatomy of elongated mutant clones.iscerning the source of spontaneous germline mutations is fundamental to understanding the causes of many diseases, including monogenic developmental disorders (1) and complex conditions such as autism (2, 3) and schizophrenia (4). Recent whole genome sequencing studies of parent-child trios show that most mutations (such as nucleotide substitutions) originate from the paternal germline and increase in frequency with the father's age (5, 6), an issue of particular significance given the demographic shift to delayed reproduction in many populations (7). The deduction that the testes of older men harbor a greater burden of mutations, compared with younger men, is consistent with indirect measures of genetic decline, ranging from high indices of arrested germ cell divisions to complete involution of the seminiferous tubules (7-9). Surprisingly, however, it has not previously been possible to trace specific mutations back to their origins within individual germ cells (spermatogonia) of human testes.One mechanism proposed to contribute to the age-related increase in male mutations is selfish spermatogonial selection, a process equivalent to neoplasia but occurring in the unique context of the germ cell (10). In this process, specific point mutations that confer gain-of-function to components of the growth factor receptor-RAS signaling pathway occur rarely in spermatogonial stem cells of the adult testis but show a steep increase in prevalence with age, attributed to clonal expansion of mutant spermatogonia over time (11)(12)(13)(14)(15)(16). Fertilization of the egg by a mutant sperm leads to serious congenital disorders in the next generation, characterized by multiple malformations and, in some cases, a predisposition to malignancy. These disorders include Apert, Crouzon, and (16, 26). Based on the unexpectedly high birth prevalence of several of the associated congenital d...

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Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case

Cited by 71 publications

References 7 publications

A case report of a patient with Pfeiffer syndrome, an FGRF 2 mutation (Trp290Cys) and unique ocular anterior segment findings

A case report of a patient with Pfeiffer syndrome, an FGRF 2 mutation (Trp290Cys) and unique ocular anterior segment findings

Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome

Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes

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