FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1991143732> ?p ?o ?g. }

• W1991143732 endingPage "1203" @default.
• W1991143732 startingPage "1202" @default.
• W1991143732 abstract "To the Editor: Ectrodactyly, ectodermal dysplasia, and clefting (EEC) syndrome (OMIM 129900) is an autosomal dominant developmental disorder, most cases of which are due to mutations in the gene encoding the transcription factor, p63 (Yang et al., 1998Yang A. Kaghad M. Wang Y. et al.p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.Mol Cell. 1998; 2: 305-316Abstract Full Text Full Text PDF PubMed Scopus (1764) Google Scholar;Celli et al., 1999Celli J. Duijf P. Hamel B.C.J. et al.Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.Cell. 1999; 99: 143-153Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). Mutations in p63 can also cause other ectodermal dysplasia syndromes, including split hand–split foot malformation, limb–mammary syndrome, and ankyloblepharon–ectodermal dysplasia–clefting syndrome, although genetic heterogeneity is known to occur in some cases (McGrath et al., 2001McGrath J.A. Duijf P. Doetsch V. et al.Hay–Wells syndrome is caused by mis-sense mutations in the SAM domain of p63.Hum Mol Genet. 2001; 10: 221-229Crossref PubMed Scopus (297) Google Scholar;van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). Nevertheless, in the EEC syndrome, the vast majority of mutations comprise heterozygous mis-sense mutations in the DNA-binding domain of p63 (van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). By contrast, p63 gene mutations in the other ectodermal dysplasia syndromes usually affect different parts of the protein. For example, ankyloblepharon–ectodermal dysplasia–clefting syndrome is typically associated with mutations in the p63 SAM domain (McGrath et al., 2001McGrath J.A. Duijf P. Doetsch V. et al.Hay–Wells syndrome is caused by mis-sense mutations in the SAM domain of p63.Hum Mol Genet. 2001; 10: 221-229Crossref PubMed Scopus (297) Google Scholar). In the few EEC syndrome mutation reports published thus far, a number of recurrent molecular abnormalities in p63 have been identified, predominantly involving mutations in 5-methylcytosine in certain CpG sites (for a recent summary seevan Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). Interestingly, the sites of these frequent p63 amino acid substitutions in EEC syndrome usually correspond to the very same residues in the p53 protein that are mutated in human cancers (Hernandez-Boussard et al., 1999Hernandez-Boussard T. Rodriguez-Tome P. Montesano R. Hainaut P.I.A.R.C. p53 mutation database. a relational database to compile and analyze p53 mutations in human tumors and cell lines.Hum Mutat. 1999; 14: 1-8Crossref PubMed Scopus (174) Google Scholar). We have searched for p63 gene mutations in six individuals thought to have EEC syndrome and our results add to the database of common mutations in that all patients had de novo mis-sense mutations in Arg304, providing new evidence that this is the most frequently mutated amino acid in this disorder. To identify mutations in p63, following informed consent, DNA was extracted from peripheral blood samples taken from the affected individuals and clinically normal parents (where possible) using a standard cold water lysis method. Individual exons of the p63 gene were amplified by polymerase chain reaction (PCR) and sequenced (van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). Specifically, to amplify exon 8 and flanking introns of p63 the following primers were used: forward primer 5′-TGGCTAAGCTGGTAGTACGT-3′, reverse primer 5′-CACAGGTCTTATCATGCAGC-3′. The expected PCR product size was 352 bp. For PCR amplification, 250 ng genomic DNA was used as the template in an amplification buffer containing 6.25 pmol of the primers, 37.5 nmol MgCl2, 5 mmol of each nucleotide triphosphate, and 1.25 U Taq polymerase (Applied Biosystems, Warrington, U.K.) in a total volume of 25 μl in an OmniGene thermal cycler (Hybaid, Basingstoke, U.K.). The amplification conditions were 94°C for 5 min, followed by 38 cycles of 94°C for 45 s, 55°C for 45 s, 72°C for 45 s. Aliquots (5 μl) of the PCR products were analyzed by 2% agarose gel electrophoresis. PCR products were then sequenced directly using Big Dye labeling in an ABI 310 genetic analyzer (Applied Biosystems). The cardinal clinical features in EEC syndrome are ectodermal dysplasia, ectrodactyly, cleft lip/palate, and nasolacrimal defects with renal anomalies, choanal atresia, and conductive deafness representing secondary features (Buss et al., 1995Buss P.W. Hughes H.E. Clarke A. Twenty-four cases of the EEC syndrome: clinical presentation and management.J Med Genet. 1995; 32: 716-723Crossref PubMed Scopus (88) Google Scholar; Roelfsema and Cobben, 1996Roelfsema N.M. Cobben J.M. The EEC syndrome a literature study.Clin Dysmorphol. 1996; 5: 115-127Crossref PubMed Scopus (112) Google Scholar). The clinical details of the individuals studied were as follows. Patient 1 was a 31 y old female with a right cleft lip and palate, fused second and third digits of the right hand with a rudimentary middle finger, left hand syndactyly, ectodermal dysplasia, and nasolacrimal duct anomalies. The ectodermal dysplasia produced nail, skin, dental, and hair defects including oligodontia with enamel hypoplasia, patchy alopecia, and dystrophic nails. No other family members were affected. Her EEC syndrome score, using established scoring criteria (Roelfsema and Cobben, 1996Roelfsema N.M. Cobben J.M. The EEC syndrome a literature study.Clin Dysmorphol. 1996; 5: 115-127Crossref PubMed Scopus (112) Google Scholar) was 12/18. Patient 2 was a 35 y old female, with a cleft palate (but no cleft lip), syndactyly of the right middle and ring fingers, left ectrodactyly, ectodermal dysplasia, and nasolacrimal drainage defects. Conductive hearing loss was present, giving an EEC score of 11/18. This individual had an affected son who was not included in this study. Patient 3 was a 4 y old boy, who had four limb ectrodactyly, cleft lip and palate, ectodermal dysplasia, and nasolacrimal defects. There was no index finger on the right hand with fusion of shortened middle and ring fingers, and in the left hand the middle finger was absent with fusion of the thumb and index finger. Both feet had cleft deformities with short fourth and fifth toes. The ectodermal dysplasia produced dry skin, patchy alopecia, and dystrophic nails. Mild conductive hearing loss was also present. The EEC syndrome score was 16/18. Patient 4 was a 4 wk old girl with no cleft lip or palate but signs of choanal atresia, ectrodactyly of the right foot, a broad right thumb with bifid tip, flexion contracture of the right index finger, syndactyly of the right middle and ring fingers, and nail hypoplasia. There was no family history of ectodermal anomalies. EEC syndrome score (to date, but lacking formal evaluation of eyes and hearing) was 7+/18. Patient 5 was a 22 wk gestation fetus, terminated following oligohydramnios and severe urogenital abnormalities detected on mid-trimester ultrasound. Autopsy findings revealed split-hand/split-foot anomalies affecting both hands and feet with missing second and third toes bilaterally. There were also signs of multicystic renal dysplasia. There was no family history of any inherited ectodermal or developmental disorders. EEC syndrome score, even allowing for lack of full-term development, was 6+/18. Patient 6 was a 34 y old female with four limb ectrodactyly, bilateral cleft lip and palate, lacrimal duct defects, conductive hearing loss, and urogenital tract anomalies. She also had evidence of mental retardation. The EEC syndrome score was 17/18. She also had a 10 y old daughter with EEC syndrome. The phenotype in the daughter, however, was much less severe with no evidence of any clefting and an overall EEC syndrome score of 7/18. Direct sequencing of DNA from these affected individuals revealed one of two point mutations in each case. In patients 1, 2, 3, 5, and 6 (and daughter) there was a heterozygous G→A substitution at nucleotide 911 within exon 8 of the p63 gene (based on nucleotide numbering of the p63α isotype with the A of the start codon as nucleotide 1). This converts an arginine residue (CGG) to glutamine (CAG) and is designated R304Q. In patient 4 there was a heterozygous C→T substitution at nucleotide 910 that converts the same arginine residue (CGG) to tryptophan (TGG) and is designated R304W. Both mutations result in the loss of a restriction site for the endonucleases HpaII or MspI (C/CGG), and this was used to verify the mutations and to establish that neither was present in amplified DNA from either parent or in 100 control chromosomes. Specifically, in amplified control DNA the 352 bp PCR product was completely digested into fragments 199 bp and 153 bp in size, but in the presence of either heterozygous mutation, R304Q or R304W, one allele remained undigested (Figure 1). No other potentially pathogenic p63 sequence variations were identified. Mutations in Arg304 have been reported in eight other families with the EEC syndrome. Along with our data, the literature now contains 10 families with R304Q (Celli et al., 1999Celli J. Duijf P. Hamel B.C.J. et al.Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.Cell. 1999; 99: 143-153Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar;van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar) and four families with R304W (Wessagowit et al., 2000Wessagowit V. Mellerio J.E. Pembroke A.C. McGrath J.A. Heterozygous germline mis-sense mutation in the p63 gene underlying EEC syndrome.Clin Exp Dermatol. 2000; 5: 441-443Crossref Scopus (36) Google Scholar;van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar) establishing this amino acid as the most common site for p63 mutations in EEC syndrome. Full clinical details have been published for 12 of these cases and, in each, the mutation has occurred de novo. This particular arginine residue has been shown to bind to DNA with direct contact to a backbone phosphate. Amino acid substitutions of Arg304 result in loss of this contact and can also impose steric hindrance on DNA binding (Celli et al., 1999Celli J. Duijf P. Hamel B.C.J. et al.Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.Cell. 1999; 99: 143-153Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar), thus impeding activity of all isoforms of p63. The heterogeneity of the clinical features in our patients with EEC syndrome is also noteworthy given the presence of the same mutated amino acid. It is evident that Arg304 mutations do not give rise to a common phenotype. Instead, it is clear that other factors, including the possible influence of other modifying genes, combine to determine the final developmental abnormalities. Similar observations have been made for other amino acid substitutions in p63. For example, mutations in Arg280 may give rise to either EEC syndrome or split hand–split foot malformation, or rarely, no detectable abnormalities (van Bokhoven et al., 2001van Bokhoven H. Hamel B.C. Bamshad M. et al.p63 gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.Am J Hum Genet. 2001; 69: 481-492Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). Collectively, these findings have important implications for genetic counseling and for the implementation of DNA-based prenatal testing in families at risk for recurrence of these disorders (South et al., 2002South A.P. Ashton G.H. Willoughby C. et al.EEC syndrome. heterozygous mutation in the p63 gene (R279H) and DNA-based prenatal diagnosis.Br J Dermatol. 2002; 146: 216-220Crossref PubMed Scopus (21) Google Scholar). Our data are also relevant to the design of strategies to detect mutations in the p63 gene in EEC syndrome. We now recommend initial PCR amplification of exon 8 and restriction endonuclease digestion with HpaII (or MspI). This will rapidly disclose the presence of either R304Q or R304W that together account for ≈ 25% of all pathogenetic p63 mutations in EEC syndrome. If no mutation is detected, analysis of the other highly mutable arginine residues in p63 (Arg204, 227, 279, and 280) should then be pursued before examining other parts of the gene. DNA and clinical information from patient 5 were kindly supplied by Whitney Neufeld-Kaiser, Eastside Maternal–Fetal Medicine Unit, Bellevue, WA. This work was supported by a project grant from the National Foundation for Ectodermal Dysplasias (NFED) and by Action Research. Additional funding for related studies on EEC syndrome from the British Medical Association and the Research and Development fund of the Royal Liverpool and Broadgreen University Hospitals is gratefully acknowledged." @default.
• W1991143732 created "2016-06-24" @default.
• W1991143732 creator A5001818255 @default.
• W1991143732 creator A5005579419 @default.
• W1991143732 creator A5014011712 @default.
• W1991143732 creator A5075070008 @default.
• W1991143732 creator A5091680581 @default.
• W1991143732 date "2002-11-01" @default.
• W1991143732 modified "2023-10-16" @default.
• W1991143732 title "Common Mutations in Arg304 of the p63 Gene in Ectrodactyly, Ectodermal Dysplasia, Clefting Syndrome: Lack of Genotype–Phenotype Correlation and Implications for Mutation Detection Strategies" @default.
• W1991143732 cites W1869756393 @default.
• W1991143732 cites W1970008001 @default.
• W1991143732 cites W2014938226 @default.
• W1991143732 cites W2033072831 @default.
• W1991143732 cites W2060823106 @default.
• W1991143732 cites W2079477526 @default.
• W1991143732 cites W2116718098 @default.
• W1991143732 cites W2116898397 @default.
• W1991143732 cites W2150715171 @default.
• W1991143732 doi "https://doi.org/10.1046/j.1523-1747.2002.19526.x" @default.
• W1991143732 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/12445213" @default.
• W1991143732 hasPublicationYear "2002" @default.
• W1991143732 type Work @default.
• W1991143732 sameAs 1991143732 @default.
• W1991143732 citedByCount "14" @default.
• W1991143732 countsByYear W19911437322012 @default.
• W1991143732 countsByYear W19911437322013 @default.
• W1991143732 countsByYear W19911437322016 @default.
• W1991143732 countsByYear W19911437322019 @default.
• W1991143732 countsByYear W19911437322022 @default.
• W1991143732 countsByYear W19911437322023 @default.
• W1991143732 crossrefType "journal-article" @default.
• W1991143732 hasAuthorship W1991143732A5001818255 @default.
• W1991143732 hasAuthorship W1991143732A5005579419 @default.
• W1991143732 hasAuthorship W1991143732A5014011712 @default.
• W1991143732 hasAuthorship W1991143732A5075070008 @default.
• W1991143732 hasAuthorship W1991143732A5091680581 @default.
• W1991143732 hasBestOaLocation W19911437321 @default.
• W1991143732 hasConcept C104317684 @default.
• W1991143732 hasConcept C127716648 @default.
• W1991143732 hasConcept C135763542 @default.
• W1991143732 hasConcept C200844832 @default.
• W1991143732 hasConcept C2776790153 @default.
• W1991143732 hasConcept C2777304866 @default.
• W1991143732 hasConcept C501734568 @default.
• W1991143732 hasConcept C54355233 @default.
• W1991143732 hasConcept C86803240 @default.
• W1991143732 hasConceptScore W1991143732C104317684 @default.
• W1991143732 hasConceptScore W1991143732C127716648 @default.
• W1991143732 hasConceptScore W1991143732C135763542 @default.
• W1991143732 hasConceptScore W1991143732C200844832 @default.
• W1991143732 hasConceptScore W1991143732C2776790153 @default.
• W1991143732 hasConceptScore W1991143732C2777304866 @default.
• W1991143732 hasConceptScore W1991143732C501734568 @default.
• W1991143732 hasConceptScore W1991143732C54355233 @default.
• W1991143732 hasConceptScore W1991143732C86803240 @default.
• W1991143732 hasIssue "5" @default.
• W1991143732 hasLocation W19911437321 @default.
• W1991143732 hasLocation W19911437322 @default.
• W1991143732 hasOpenAccess W1991143732 @default.
• W1991143732 hasPrimaryLocation W19911437321 @default.
• W1991143732 hasRelatedWork W1530402712 @default.
• W1991143732 hasRelatedWork W1980121404 @default.
• W1991143732 hasRelatedWork W1991143732 @default.
• W1991143732 hasRelatedWork W2125731289 @default.
• W1991143732 hasRelatedWork W2132993604 @default.
• W1991143732 hasRelatedWork W2143066563 @default.
• W1991143732 hasRelatedWork W2149447718 @default.
• W1991143732 hasRelatedWork W2157166663 @default.
• W1991143732 hasRelatedWork W3032357680 @default.
• W1991143732 hasRelatedWork W4319333460 @default.
• W1991143732 hasVolume "119" @default.
• W1991143732 isParatext "false" @default.
• W1991143732 isRetracted "false" @default.
• W1991143732 magId "1991143732" @default.
• W1991143732 workType "article" @default.