Study of four genes belonging to the folate pathway: transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate

Abstract

Cleft lip with or without cleft palate (CL/P) is the most common inborn craniofacial anomaly. Affected individuals require extensive medical and psychosocial support. Although CL/P has a complex and poorly understood etiology, increasing evidence of folate pathway involvement has been collected. So far, only the MTHFR gene has been extensively investigated as a risk factor for CL/P, while little has been done to test genetic variations in the folate biosynthetic pathways that may influence the infant's susceptibility to these birth defects. To date, this paper presents the first attempt to verify the involvement of four genes belonging to the folate pathway in nonsyndromic cleft onset. We used a case-parent triad design to test for linkage disequilibrium in the case of seven SNPs mapping on four different genes: transcobalamin 1 and 2 (TCN1 and TCN2), methionine synthase (MTR), and MTR reductase (MTRR). Our finding suggests that TCN2 is involved in causing CL/P. Indeed, significant overtransmission of the C allele was observed at the polymorphism c.776C>G (p.Pro259Arg) to the affected offspring (P=0.01). Results obtained with additional TCN2 polymorphisms suggest that c.776C>G may be functionally related to CL/P. However, because conflicting data exist with regard to the effect of the polymorphism in transcobalamin 2 function or in perturbing plasma levels of key molecules in the folate pathway, further investigation is warranted to confirm our data.

Efficacy of a New Coating of Implantabutment Connections in Reducing Bacterial Loading: An in Vitro Study

“…Peri-implantitis can happen with high frequencies in bone regeneration (60-63) also after cancer resection (64)(65)(66)(67)(68). In some pediatric conditions can be useful to have a low bacterial loading (69)(70)(71)(72)(73)(74)(75)(76)(77). During the prosthetic rehabilitation, bacterial dissemination is unavoidable, and when the IAJ is located at the level of the bone crest, the formation of biofilms in this area causes bone resorption, observed in the early stages of prosthetic load.…”

New Insights in Orofacial Cleft: Epidemiological and Genetic Studies on Italian Samples

“…Mutations in interferon regulatory factor 6 (IRF6) can lead to Van der Woude syndrome, a dominant disorder that has CL±P as a common feature. Recently, it has been proposed and confirmed a strong association between genetic polymorphisms at the IRF6 locus, on 1p32.2 and CL±P, particularly in Asian and South American populations (26,(28)(29)(30)(31). Moreover, MYH9, a gene encoding for the heavy chain of non-muscle myosin IIA, is also considered a potential candidate in the CL±P onset.…”

“…The results of these study highlight that polymorphic variants at the MTHFR gene are responsible for a higher risk of having L±PC affected children. Folate receptors (FOLRs) mediate the delivery of 5-methyltetrahydrofolate to the interior of cells or between cells in a process known as potocytosis (20,28,29). In order to verify whether FOLRs could be involved in the onset of non-syndromic CL±P, a sample study consisted of patients and their mothers from 71 CL±P families and 75 sporadic cases was tested using linkage and linkage disequilibrium analyses.…”

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Nonsyndromic Cleft Lip and/or Palate

“…It was not found an association between TCN2 (776C>G) and NSCL/P. Martinelli et al (11) investigated the association between NSCL/P and TCN2 (776C>G) gene in a case-parent triad and they suggested that this polymorphism might be functionally related with NSCL/P. On the other hand, later studies tried to replicate their findings, but could not confirm this association (10).…”