Methylenetetrahydrofolate reductase thermolabile variant and oral clefts

Mills, James L.; Kirke, Peadar N.; Molloy, Anne M.; Burke, Helen; Conley, Mary; Lee, Young Jack; Mayne, Philip; Weir, Donald G.; Scott, John M.

doi:10.1002/(sici)1096-8628(19990903)86:1<71::aid-ajmg14>3.3.co;2-p

Cited by 36 publications

(49 citation statements)

References 15 publications

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“…In this regard, using the case-control design, Tolarova et al [88] first observed that homozygotes for the 677 T allele were three times more frequent in CL/P Argentinean patients than in controls. However, these findings were not confirmed by most of the subsequent studies using California [89], Brazil [90], Polish [91] and Irish [92] population samples. However, in an, homozygosity for the C677T allele was associated with an increased risk for isolated cleft palate (OR =3.2; 95 percent CI: 1.3, 7.9) and possibly for cleft lip with or without cleft palate (OR =1.6; 95 percent CI: 0.8, 3.4) [92].…”

Section: Association Studiesmentioning

confidence: 63%

“…However, these findings were not confirmed by most of the subsequent studies using California [89], Brazil [90], Polish [91] and Irish [92] population samples. However, in an, homozygosity for the C677T allele was associated with an increased risk for isolated cleft palate (OR =3.2; 95 percent CI: 1.3, 7.9) and possibly for cleft lip with or without cleft palate (OR =1.6; 95 percent CI: 0.8, 3.4) [92]. An increased risk due to the maternal MTHFR genotype (677 T or 1282A alleles) on predisposition to CL/P was suggested by several studies [14,93,94,95,96].…”

Section: Association Studiesmentioning

confidence: 63%

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Molecular Genetics of Non-Syndromic Clefts Revisited

Rajasekhar¹,

Lakkakula²,

KS³

2011

Int J Genet

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Cleft of the lip and palate (CL/P) are generally divided in to two groups, isolated cleft palate and cleft with or without cleft palate representing a heterogeneous group of disorders affecting the upper lip and the roof the mouth. Non-syndromic cleft lip and palate incidence is 1 in 700 to 1000 live babies with ethnic and geographic variations. Various independent association and linkage studies using different populations have identified several loci. Numerous genes have been reported in studies demonstration associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factor, growth factor, cell signalling and detoxification metabolisms. Currently, efforts are focussed to identify the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype. In conclusion, the genetic basis of CL/P is still contentious because of genetic complexity of clefting.

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Section: Association Studiesmentioning

confidence: 63%

Section: Association Studiesmentioning

confidence: 63%

Molecular Genetics of Non-Syndromic Clefts Revisited

Rajasekhar¹,

Lakkakula²,

KS³

2011

Int J Genet

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“…The T allele frequency of 3.9% did not differ from the frequency in the general Brazilian population (Arruda et al, 1998). Previous studies on the association between C677T polymorphism and NS-CL/P produced contradictory results (Shaw et al, 1995(Shaw et al, , 1996(Shaw et al, , 1998Tolarova and Cervenka, 1998;Gaspar et al, 1999;Mills et al, 1999;Blanton et al, 2000Blanton et al, , 2002Wyszynski and Diehl, 2000;Martinelli et al, 2001;Prescott et al, 2002;van Rooij et al, 2003).…”

mentioning

confidence: 73%

“…The etiology is complex, including multiple genetic and environmental factors. The MSX1 and TGFB3 genes have been suggested as candidate genes based on animal models (Satokata and Maas, 1994;Kaartinen et al, 1995;Proetzel et al, 1995) and association studies in humans with genes MSX1, TGFB3 and MTHFR have pointed to the involvement of these genes in NS-CL/P etiology (Maestri et al, 1997;Lidral et al, 1998;Romitti et al, 1999;Mills et al, 1999; Wyszynsky and Diehl, 2000;Beaty et al, 2001). The MSX1 gene maps to chromosome 4p16.…”

mentioning

confidence: 99%

Transmission analysis of candidate genes for nonsyndromic oral clefts in Brazilian parent-child triads with recurrence

Silva¹,

Ribeiro²,

Cooper³

et al. 2006

Genet. Mol. Biol.

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Cleft lip and/or palate (CL/P) is a major congenital defect with complex etiology, including multiple genetic and environmental factors. Approximately two thirds of the cases are not accompanied by other anomalies and are called nonsyndromic (NS). In the present study, we performed transmission distortion analysis of the MSX1-CA, TGFB3-CA and MTHFR-C677T polymorphisms in 60 parent-child triads, in which the NS-CL/P affected child had at least one affected parent. No association with genes MSX1 or TGFB3 was found, but the results were suggestive of an association of the MTHFR-C677T polymorphism with NS-CL/P. Nonsyndromic cleft lip and/or palate (NS-CL/P) affect about 1/700 livebirths, with wide variability concerning geographic distribution, ethnic background and socioeconomic status (Murray, 2002). The etiology is complex, including multiple genetic and environmental factors. The MSX1 and TGFB3 genes have been suggested as candidate genes based on animal models (Satokata and Maas, 1994;Kaartinen et al., 1995;Proetzel et al., 1995) and association studies in humans with genes MSX1, TGFB3 and MTHFR have pointed to the involvement of these genes in NS-CL/P etiology (Maestri et al., 1997;Lidral et al., 1998;Romitti et al., 1999;Mills et al., 1999; Wyszynsky and Diehl, 2000;Beaty et al., 2001). The MSX1 gene maps to chromosome 4p16. Animal models indicate that this gene plays a role in craniofacial anomalies, leading to a clefting phenotype. Van den Boogaard et al. (2000) identified a stop codon in the MSX1 gene in a three-generation Dutch family with tooth agenesis and combinations of CP only and CLP, providing further evidence for the involvement of this gene in orofacial clefting. Jezewski et al. (2003) sequenced the whole MSX1 gene in a large sample of NS-CL/P patients from different geographic regions, and found mutations in about 2% of the cases.The TGFB3 gene maps to 14q24. Animal model studies demonstrated that TGFB3 plays a role in CP (Kaartinen et al., 1995;1997;Proetzel et al., 1995; Sanford et al., 1997), andLidral et al. (1998) showed an association between TGFB3 markers and NS-CP.The MTHFR gene maps to 1p36.1, and plays a key role in the metabolism of folate by reducing methylenetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis. The C677T nucleotide variant in the MTHFR gene results in a thermally unstable protein with reduced activity, leading to elevated plasma homocysteine levels. Considerable heterogeneity in the prevalence of the C677T polymorphism throughout the world was reported (Pepe et al., 1998).The present work aimed to investigate if genes TGFB3, MSX1 and MTHFR-C677T are involved in the etiology of NS-CLP, by testing 60 patients, all with an affected parent. We utilized a nuclear family-based approach, to determine for each form of clefting whether these genes were in linkage disequilibrium, as measured by transmission distortion.A total of 60 triads, each one including an affected child and at least one affected parent, were studied. Of...

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“…Animal studies suggest that a decreased conversion of homocysteine to methionine could be a crucial step in causing neural tube defects. It has been shown that rat embryos in culture require methionine for neural tube closure (Mills et al, 1999).…”

Section: Approximatelymentioning

confidence: 99%