A genetic study of the human T gene and its exclusion as a major candidategene for sacral agenesis with anorectal atresia

Sacral agenesis is a heterogeneous group of congenital anomalies in which m ost cases are sporadic but rare familial forms also occur. Although one gen e has been mapped to chromosome 7q36 in families with hemisacrum, associate d with anorectal atresia and presacral mass, it is clear that the genetic a etiology of these disorders is complex and other genes remain to be discove red. Some years ago, the idea of T (Brachyury) as a candidate gene for sacr al agenesis was raised, because tail abnormalities associated with T and th e t complex, on mouse chromosome 17, resemble spinal defects seen in man. T he recent cloning and mapping of the human T gene prompted us to re-evaluat e this idea. T is a transcription factor essential for the normal developme nt of posterior mesodermal structures. Although the sequence and function o f T are highly conserved in evolution, our genetic study shows that the cod ing region of the human gene is highly polymorphic. Three common variable a mino acid sites in known functional domains have been identified: Gly356Ser , Asn369Ser, and Gly177Asp. For the latter variant, functional studies have shown that the presence of Asp at residue 177 reduces the stability of T d imer formation. A search for rare mutation of T in 28 selected patients wit h sacral agenesis/anorectal atresia identified a novel, rare variant in one patient and her mother. This mutation leads to an amino acid change within a conserved activation domain. While the functional significance of this s ingle mutation requires further investigation, we can conclude fit om our s tudies that if T has a role in the aetiology of sacral agenesis, its contri bution is small in this particular set of patients. However, we cannot excl ude a more major role in other forms of sacral defect.