A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23

Abstract

Williams syndrome (WS) is a developmental disorder with a characteristic personality and cognitive profile that is associated, in most cases, with a 2 Mb deletion of part of chromosome band 7q11.23. By applying CpG island cloning methods to cosmids from the deletion region, we have identified a new gene, called FZD3. Dosage blotting of DNA from 11 WS probands confirmed that it is located within the commonly deleted region. Sequence comparisons revealed that FZD3, encoding a 591 amino acid protein, is a novel member of a seven transmembrane domain receptor family that are mammalian homologs of the Drosophila tissue polarity gene frizzled. FZD3 is expressed predominantly in brain, testis, eye, skeletal muscle and kidney. Recently, frizzled has been identified as the receptor for the wingless (wg) protein in Drosophila. We show that Drosophila as well as human cells, when transfected with FZD3 expression constructs, bind Wg protein. In mouse, the wg homologous Wnt1 gene is involved in early development of a large domain of the central nervous system encompassing much of the midbrain and rostral metencephalon. The potential function of FZD3 in transmitting a Wnt protein signal in the human brain and other tissues suggests that heterozygous deletion of the FZD3 gene could contribute to the WS phenotype.

A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome

“…12 Other genes since identified are shown in Table 1. [13][14][15][16][17][18][19][20][21][22] All these genes appear to be deleted in most WS patients. No phenotype has been clearly assigned to haploinsufficiency for any of them and some are deleted in patients ascertained through SVAS who do not have WS.…”

Frizzled-9 Is Activated by Wnt-2 and Functions in Wnt/β-Catenin Signaling

“…In the present study, we characterize a recently identified Frizzled family member, Frizzled-9, in Wnt/␤-catenin signaling. Frizzled-9 is highly expressed in the brain, and its gene is one of several genes that are deleted in a developmental disorder, Williams syndrome (29,30). The gene deletion is thought to contribute to the neurological symptoms of Williams syndrome (29,30).…”

“…Frizzled-9 is highly expressed in the brain, and its gene is one of several genes that are deleted in a developmental disorder, Williams syndrome (29,30). The gene deletion is thought to contribute to the neurological symptoms of Williams syndrome (29,30). We demonstrate that rat Frizzled-9 (Rfz9) functions in Wnt/␤-catenin signaling in mammalian cells and that Rfz9 can act as a receptor for Wnt-2.…”

Radiation hybrid mapping of genes in the lithium-sensitive Wnt signaling pathway

“…29 Frizzled 3 which is expressed in highest levels in adult brain 7 was previously shown to be located within the 2-Mb deletion region of chromosome band 7q11.23 that was associated with the developmental disorder, Williams syndrome (WS). 30 The deleted sequence within chromosome band, 7q11.23, encodes frizzled 3 that may contribute to the WS phenotype. 30 RHM indicated that frizzled 3 was most closely linked to a marker D7S2101E, at 7q11.21.…”

“…30 The deleted sequence within chromosome band, 7q11.23, encodes frizzled 3 that may contribute to the WS phenotype. 30 RHM indicated that frizzled 3 was most closely linked to a marker D7S2101E, at 7q11.21. This linked marker was located 40 cR from locus D7S672 that was more proximal to the telomeric end of chromosome 7q.…”