[show abstract][hide abstract] ABSTRACT: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are the most common hereditary causes of visual impairment in infants and children. Using homozygosity mapping, we narrowed down the critical region of the LCA3 locus to 3.8 Mb between markers D14S1022 and D14S1005. By direct Sanger sequencing of all genes within this region, we found a homozygous nonsense mutation in the SPATA7 gene in Saudi Arabian family KKESH-060. Three other loss-of-function mutations were subsequently discovered in patients with LCA or juvenile RP from distinct populations. Furthermore, we determined that Spata7 is expressed in the mature mouse retina. Our findings reveal another human visual-disease gene that causes LCA and juvenile RP.
The American Journal of Human Genetics 04/2009; 84(3):380-7. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: dachshund/Dach gene family members encode transcriptional cofactors with highly conserved protein interaction domains and are expressed in the developing eyes, brains, and limbs in insects and vertebrates. These observations suggest that the developmental roles of dachshund/Dach in these tissues have been conserved since the divergence of arthropods and chordates. However, while Drosophila dachshund mutants have abnormalities in eye, brain, limbs, mouse Dach1 or Dach2 knockout mutants do not exhibit gross anatomical malformations in these tissues. In addition, Dach1/2 double homozygotes have intact eyes and limbs. Here we show that in Dach1/Dach2 double mutants, female reproductive tract (FRT) development is severely disrupted. This defect is associated with the Müllerian duct (MD) and not the Wolffian duct (WD), which normally differentiate into either the FRT or male reproductive tract (MRT), respectively. Dach1 and Dach2 are expressed in the MD, and in Dach1/2 double mutants, MD expression of Lim1 and Wnt7a is abnormal and MD development is disrupted. In contrast, WD and MRT development are not grossly affected. We propose that Dach1 and Dach2 proteins may redundantly control FRT formation by regulating the expression of target genes required for development of the MD. This vertebrate Dach1/2 function may have been conserved during arthropod evolution, as Drosophila dachshund mutants also exhibit an FRT phenotype.