With an average worldwide prevalence of 1/800 live births, oral clefts are one of the most common birth defects. Although over 300 malformation syndromes can include an oral cleft, non-syndromic forms represent about 70% of cases with cleft lip with or without cleft palate (CL/P) and roughly 50% of cases with cleft palate (CP) only. Non-syndromic oral clefts are considered ‘complex’ or ‘multifactorial’ in that both genes and environmental factors contribute to the etiology. Current research suggests that several genes are likely to control risk, as well as environmental factors such as maternal smoking.
Re-sequencing studies to identify specific mutations suggest several different genes may control risk to oral clefts, and many distinct variants or mutations in apparently causal genes have been found reflecting a high degree of allelic heterogeneity. Although most of these mutations are extremely rare and often show incomplete penetrance (i.e., an unaVected parent or other relative may also carry the mutation), combined they may account for up to 5% of non-syndromic oral cleft.
Mutations in the SATB2 gene have been found to cause isolated cleft palates. SATB2 also likely influences brain development. This is consistent with mouse studies that show SATB2 is necessary for proper establishment of cortical neuron connections across the corpus callosum, despite the apparently normal corpus callosum in heterozygous knockout mice.
SATB2 is a 733 amino-acid homeodomain-containing human protein with a molecular weight of 82.5 kDa encoded by the SATB2 gene on 2q33. The protein contains two degenerate homeodomain regions known as CUT domains (amino acid 352–437 and 482–560) and a classical homeodomain (amino acid 614–677). There is an extraordinarily high degree of sequence conservation, with only three predicted amino-acid substitutions in the 733 residue protein with I481V, A590T and I730T being amino acid differences between the human and the mouse protein.
SATB2 was found to be disrupted in two unrelated cases with de novo apparently balanced chromosome translocations associated with cleft palate and Pierre Robin Sequence.
The role of SATB2 in tooth and jaw development is supported by the identification of a de novo SATB2 mutation in a male with profound mental retardation and jaw and tooth abnormalities and a translocation interrupting SATB2 in an individual with Robin sequence. In addition, mouse models have demonstrated haploinsufficiency of SATB2 results in craniofacial defects that phenocopy those caused by 2q32q33 deletion in humans; moreover, full functional loss of SATB2 amplifies these defects.
^Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (June 1999). "Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Res.6 (3): 197–205. doi:10.1093/dnares/6.3.197. PMID10470851.
Dobreva G, Chahrour M, Dautzenberg M, et al. (2006). "SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation.". Cell125 (5): 971–86. doi:10.1016/j.cell.2006.05.012. PMID16751105.
Beaty TH, Hetmanski JB, Fallin MD, et al. (2006). "Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations.". Hum. Genet.120 (4): 501–18. doi:10.1007/s00439-006-0235-9. PMID16953426.
Machado RD, Pauciulo MW, Fretwell N, et al. (2000). "A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium.". Genomics68 (2): 220–8. doi:10.1006/geno.2000.6291. PMID10964520.