Disease relevance of OFC1

• An allelic association between the transforming growth factor alpha gene (TGFA) situated in the chromosome 2p13 region and nonsyndromic cleft lip with or without cleft palate, also named orofacial cleft (OFC), was found in several population studies [1].
• Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000 [2].
• Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive [3].
• Expression studies of fusion proteins lacking the collagen and N-terminal domains produced in Escherichia coli affirmed that CL-L1 binds mannose weakly [4].
• Genetic studies in families of patients with neural-tube defects and cleft lip (CL), with and without cleft palate (CP), as well as genetic studies in families of patients with epilepsy, show evidence for the possible existence of genes on the short arm of chromosome 6 [5].

Psychiatry related information on OFC1

• OBJECTIVE: Patients with major depressive disorder (MDD) treated with olanzapine in combination with fluoxetine (OFC) demonstrate robust improvement in their depressive symptoms [6].
• OBJECTIVE: To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes [7].
• We report on a family with X-linked hydrocephalus: progressive increase in head circumference (OFC) led to the diagnosis in 3 patients; however, in 5 with normal OFC, the initial diagnosis had been "nonspecific" mental retardation, until identification of relatedness between 3 macrocephalic boys suggested segregation of a major Mendelian gene [8].
• A trend towards risk reduction for OFC with increasing dietary intake was demonstrated for thiamine (p = 0.04) and pyridoxine (p = 0.03) [9].
• Regional and antigen-specific down-regulation of GFAP protein in OFC in schizophrenia and bipolar disorder may relate to disease mechanisms of psychosis [10].

High impact information on OFC1

• We derived data from a population-based case-control study of fetuses and liveborn infants with orofacial anomalies among a 1987-89 cohort of births in California. We interviewed 731 (84.7%) of eligible mothers with orofacial cleft case infants and 734 (78.2%) mothers with non-malformed control infants [11].
• A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6) [12].
• Change of rCBF within the left amygdala and the left OFC was highly intercorrelated, indicating a strong functional interaction between these brain regions [13].
• Ninety extended families having one or more individuals affected with nonsyndromic cleft lip (CL) with or without cleft palate (CL/P) were ascertained in rural West Bengal, India. These families included 138 affected people, 64% of whom had CL alone and 66% of whom were male [14].
• In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47) [15].

Chemical compound and disease context of OFC1

• Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper [16].
• The risk of weight gain may be significantly increased for OFC-treated patients who have a low BMI or who are female, younger, or taking high-dose fluoxetine [6].
• The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate [17].
• METHODS: In this case-control study of 45 mothers of orofacial cleft children, 39 mothers of spina bifida children and 73 control mothers, NAT2 acetylator status was determined by measuring urinary caffeine metabolites [18].
• RESULTS: Customised birthweight centile of 10 or less had the following LR values for the various anthropometric criteria for IUGR: 5.1 (95% CI 3-8.5) for low skinfold thickness; 4.3 (95% CI 2.5-7.1) for low ponderal index; and 3.9 (95% CI 2-6.6) for low MAC/OFC ratio [19].

Biological context of OFC1

• Genetic heterogeneity has been observed in CL+/-P, which involves different chromosome regions, mainly 6p23 (OFC1), 2q13 (OFC2), and 19q13.2 (OFC3), as well as other loci, such as 4q25-4q31.3 and 17q21 [20].
• Previously, we employed a collection of 38 OFC families to demonstrate linkage to the 6p23 chromosome region with the presence of genetic heterogeneity [1].
• For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P [2].
• Because serum folate may be decreased by cigarette smoking and because maternal periconceptional use of multivitamins containing folic acid has been associated with a reduced risk of clefting, we explored whether a potential relation existed between infant TGFa genotype, maternal multivitamin use, and risk of orofacial cleft phenotypes [21].
• The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci [2].

Anatomical context of OFC1

• Ventrolateral Prefrontal Cortex/Orbitofrontal Cortex (VLPFC/OFC) was active when specific strategic task rule and outcome information was available [22].
• Analysis of CL-deficient mice revealed a profound defect in invariant chain degradation in thymic cortical epithelial cells but not in bone marrow-derived antigen-presenting cells (APCs) (B cells, dendritic cells, and macrophages) [23].
• Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions [24].
• More sensitive analyses by reverse transcription-polymerase chain reactions showed that most tissues (except skeletal muscle) have CL-L1 mRNA [4].
• These transcripts share a similar upstream sequence region and extend downstream to include a CL or alternatively a JL segment in partial germ-line configuration that has been spliced into a CL [25].

Associations of OFC1 with chemical compounds

• Here we report the cloning of a cDNA encoding human collectin from liver (CL-L1 (collectin liver 1)) that has typical collectin structural characteristics, consisting of an N-terminal cysteine-rich domain, a collagen-like domain, a neck domain, and a carbohydrate recognition domain [4].
• Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring [26].
• To investigate the molecular consequence of loading free cholesterol into macrophages, we conducted a large-scale gene expression study to analyze acetylated-LDL-laden foam cells (AFC) and oxidized-LDL-laden foam cells (OFC) induced from human THP-1 cell lines [27].
• Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk [26].
• Phenytoin also causes CL if administered to pregnant rats during the period of early facial development [17].

Physical interactions of OFC1

• We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft [28].

Other interactions of OFC1

• In one case at least, an OFC1 and OFC2 interaction has been demonstrated [20].
• EDN1 maps to the chromosomal region of the OFC1 locus in 6p23 [29].
• Different roles of the TGFA and BCL3 genes in the susceptibility to NS-OFC phenotypes are suggested [30].
• No interaction between maternal NAT2 acetylator status and smoking or medication use was observed for orofacial cleft and spina bifida risk [18].
• Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, being characterised by variable association of lower lip pits, cleft lip and cleft palate [31].

Analytical, diagnostic and therapeutic context of OFC1

• The development of animal models allowed to confirm the genetic bases of CL/P, or CP, exemplify the role of teratogens, and study the interaction of nature and nurture [32].
• The present fMRI study examined effective connectivity within an emotional network composed of three brain areas: Amygdala (AMY), Anterior Cingulate Cortex (AAC) and Orbito-Frontal (OFC) in processing fearful faces [33].
• Molecular cloning of a novel human collectin from liver (CL-L1) [4].
• Genomic Southern blot analyses with VL and CL probes indicate that there are at least 30 VL segments and at least 15 CL segments [25].
• Northern blot, Western blot, and reverse transcription-polymerase chain reaction analyses showed that CL-L1 is present mainly in liver as a cytosolic protein and at low levels in placenta [4].

References