PMID- 10204846
OWN - NLM
STAT- MEDLINE
DCOM- 19990611
LR  - 20220419
IS  - 0022-2593 (Print)
IS  - 0022-2593 (Linking)
VI  - 36
IP  - 3
DP  - 1999 Mar
TI  - A genetic study of the human T gene and its exclusion as a major candidate gene
      for sacral agenesis with anorectal atresia.
PG  - 208-13
AB  - Sacral agenesis is a heterogeneous group of congenital anomalies in which most
      cases are sporadic but rare familial forms also occur. Although one gene has been
      mapped to chromosome 7q36 in families with hemisacrum, associated with anorectal 
      atresia and presacral mass, it is clear that the genetic aetiology of these
      disorders is complex and other genes remain to be discovered. Some years ago, the
      idea of T (Brachyury) as a candidate gene for sacral agenesis was raised, because
      tail abnormalities associated with T and the t complex, on mouse chromosome 17,
      resemble spinal defects seen in man. The recent cloning and mapping of the human 
      T gene prompted us to re-evaluate this idea. T is a transcription factor
      essential for the normal development of posterior mesodermal structures. Although
      the sequence and function of T are highly conserved in evolution, our genetic
      study shows that the coding region of the human gene is highly polymorphic. Three
      common variable amino 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 dimer formation. A search for rare mutation of T in 28 selected
      patients with 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 single
      mutation requires further investigation, we can conclude from our studies that if
      T has a role in the aetiology of sacral agenesis, its contribution is small in
      this particular set of patients. However, we cannot exclude a more major role in 
      other forms of sacral defect.
FAU - Papapetrou, C
AU  - Papapetrou C
AD  - MRC Human Biochemical Genetics Unit, University College London, UK.
FAU - Drummond, F
AU  - Drummond F
FAU - Reardon, W
AU  - Reardon W
FAU - Winter, R
AU  - Winter R
FAU - Spitz, L
AU  - Spitz L
FAU - Edwards, Y H
AU  - Edwards YH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fetal Proteins)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (Transcription Factors)
RN  - EQ43SC3GDB (Brachyury protein)
SB  - IM
MH  - Anus, Imperforate/*genetics
MH  - DNA-Binding Proteins/*genetics
MH  - *Fetal Proteins
MH  - Humans
MH  - Polymorphism, Genetic
MH  - Sacrum/*abnormalities
MH  - *T-Box Domain Proteins
MH  - Transcription Factors/*genetics
PMC - PMC1734318
EDAT- 1999/04/16 00:00
MHDA- 1999/04/16 00:01
CRDT- 1999/04/16 00:00
PHST- 1999/04/16 00:00 [pubmed]
PHST- 1999/04/16 00:01 [medline]
PHST- 1999/04/16 00:00 [entrez]
PST - ppublish
SO  - J Med Genet. 1999 Mar;36(3):208-13.