Mutations in PITX2 may contribute to cases of omphalocele and VATER-like syndromes.
Omphalocele is a congenital anomaly with substantial morbidity. Rieger syndrome, an autosomal dominant disorder, is characterized by craniofacial abnormalities and abdominal wall defects. PITX2 mutations are etiologic in >40% of cases of Rieger syndrome. We demonstrate that the birth prevalence of omphalocele is significantly higher in Rieger syndrome than in the general population, with omphaloceles found in 0.03% in the Iowa newborn population and 4.3% of patients with Rieger syndrome. Our objective was to screen coding and conserved non-coding regions of PITX2 for mutations in 209 patients with omphalocele. We identified remarkable evolutionarily conserved regions by comparing the 3'UTR of Pitx2 in 13 vertebrate and 3 invertebrate species. No mutations changing the amino acid sequence were found within the omphalocele population. In one case of omphalocele with VATER-like additional anomalies, a three nucleotide deletion was found in the 3'UTR. This deletion was not seen in 1,186 controls. Also in the 3'UTR, we identified a single nucleotide polymorphism at a highly conserved residue. Our findings suggest additional studies of PITX2 conserved regions will be valuable. We also screened the omphalocele cases for mutations in exon 5 of the gene FLNA. Mutations in FLNA have been shown to cause a broad range of congenital malformations, including otopalatodigital syndrome type 2 in which a missense mutation occurring in exon 5 of FLNA results in omphalocele as part of the phenotype. We did not find any mutations in exon 5 of FLNA in 179 omphalocele cases studied.
Katz
L A
LA
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
Schultz
R E
RE
Semina
E V
EV
Torfs
C P
CP
Krahn
K N
KN
Murray
J C
JC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D006554:Hernia, Umbilical / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2