WNT5A mutations in patients with autosomal dominant Robinow syndrome.
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.
Person
Anthony D
AD
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Beiraghi
Soraya
S
Sieben
Christine M
CM
Hermanson
Spencer
S
Neumann
Ann N
AN
Robu
Mara E
ME
Schleiffarth
J Robert
JR
Billington
Charles J
CJ
van Bokhoven
Hans
H
Hoogeboom
Jeannette M
JM
Mazzeu
Juliana F
JF
Petryk
Anna
A
Schimmenti
Lisa A
LA
Brunner
Han G
HG
Ekker
Stephen C
SC
Lohr
Jamie L
JL
D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013577:Syndrome; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071818:Wnt-5a Protein; D014981:Xenopus; D015027:Zebrafish
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors