Article

WNT5A mutations in patients with autosomal dominant Robinow syndrome.

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Developmental Dynamics (Impact Factor: 2.67). 11/2009; 239(1):327-37. DOI: 10.1002/dvdy.22156
Source: PubMed

ABSTRACT Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia, and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown; however, the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here, we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function.

1 Bookmark
 · 
242 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Robinow syndrome (RS) is a clinically and genetically heterogenous condition primarily characterized by short stature, mesomelia, genital hypoplasia, oral abnormalities, and a facial gestalt that includes hypertelorism, a short nose, and a broad mouth. The disorder exists in both a dominant and a more severe recessive form. Here two unrelated cases of sporadic RS are described with the additional finding of axial and appendicular osteosclerosis. These two patients, coupled with three additional patients previously described in the literature, may represent a distinct sub-phenotype of this condition. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2014; 164(10). · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UB) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the Gdnf expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in mesoderm with an inducible Cre at E7.5 results in duplex UBs; whereas, ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role for Wnt5a/Ror2 signaling in IM extension and offers new insight into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations.
    Human Molecular Genetics 07/2014; · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The diversity of populations in domestic species offers great opportunities to study genome response to selection. The recently published Sheep HapMap dataset is a great example of characterization of the world wide genetic diversity in sheep. In this study, we re-analyzed the Sheep HapMap dataset to identify selection signatures in worldwide sheep populations. Compared to previous analyses, we made use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of linkage disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows pinpointing several new selection signatures in the sheep genome and distinguishing those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the ones previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments.
    PLoS ONE 08/2014; 9(8):e103813. · 3.53 Impact Factor

Full-text

Download
84 Downloads
Available from
May 31, 2014