Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Mansilla, M. Adela; Cooper, Margaret E.; Goldstein, Toby; Castilla, Eduardo E.; Camelo, Jorge López; Marazita, Mary L.; Murray, Jeffrey C.

doi:10.1597/04-169

Cited by 29 publications

(34 citation statements)

References 15 publications

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“…GLI2 is a member of the GLI-Kruppel family of zinc Wnger proteins and appears to be an obligatory mediator of Sonic Hedgehog (SHH) signaling pathway, which activates expression of the PTCH gene. Mansilla et al (2006) recently reported variants in PTCH showed evidence of linkage and disequilibrium with oral clefts in a sample of Filipino multiplex families.…”

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confidence: 96%

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

et al. 2006

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Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

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confidence: 96%

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

et al. 2006

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“…Gorlin syndrome for example is caused by mutations in PTCH and is associated with cleft palate in 5% of cases (Evans et al , 1993). Because of this association with clefts, PTCH was examined for mutations in cases of isolated CL/P (Mansilla et al , 2006). Two missense mutations were found in the extracellular loops of PTCH , predicted to interfere with SHH binding.…”

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confidence: 99%

The genetics of isolated orofacial clefts: from genotypes to subphenotypes

2009

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Orofacial clefts are the most common craniofacial birth defects and one of the most common congenital malformations in humans. They require complex multidisciplinary treatment and are associated with elevated infant mortality and significant lifelong morbidity. The development of craniofacial structures is an exquisitely orchestrated process involving the coordinated growth of multiple, independently derived primordia. Perturbations impacting on the genesis or growth of these primordia may interfere with the proper morphogenesis of facial structures, resulting in clefting of the lip, the primary or secondary palate, or a combination of these sites. A variety of genetic approaches involving both human populations and animal models have greatly facilitated the search for genes involved in human clefting. In this article, we review the most prominent genes for orofacial clefts in the context of developmental pathways that shape the craniofacial complex. We highlight several Mendelian clefting syndromes that have provided valuable clues in identifying genes for the more common, isolated forms of clefting. Finally, we elaborate on a number of potential subclinical features (subphenotypes) associated with what have previously been diagnosed as ‘isolated’ clefts that may serve as additional markers for identifying individuals or families in whom there may be a greater risk of inheriting a cleft.

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“…Genome-wide linkage studies have revealed that the region 9q21 has significant linkage with facial clefting (Marazita et al, 2004). A number of candidate genes for CL/P in this region, 9q21–23, have been reported previously ( ROR2, PTCH, FOXE1 , and TGFBR1 ) (Ichikawa et al, 2006; Loeys et al, 2006; Mansilla et al, 2006; Mizuguchi et al, 2004; van Bokhoven et al, 2000; Vieira et al, 2005). Using a positional cloning approach, we demonstrated that SLC31A1 on chromosome 9 was disrupted within its intron.…”

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confidence: 70%

Searching for Genes for Cleft Lip and/or Palate Based on Breakpoint Analysis of a Balanced Translocation t(9;17)(q32;q12)

Machida

Félix

Murray

et al. 2009

The Cleft Palate Craniofacial Journal

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Objective-Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate.Methods-We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations.Results-Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17.Conclusions-The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development.

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Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Cited by 29 publications

References 15 publications

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

The genetics of isolated orofacial clefts: from genotypes to subphenotypes

Searching for Genes for Cleft Lip and/or Palate Based on Breakpoint Analysis of a Balanced Translocation t(9;17)(q32;q12)

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