WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting several systems caused by a heterozygous deletion in the chromosomal region 7q11.23. A common interval that includes up to 17 genes reported so far is deleted in the great majority of patients. Elastin haploinsufficiency is responsible for the cardiovascular features, but the specific contribution of other deleted genes to the WBS phenotype remains unknown. We have fully characterised a gene commonly deleted in WBS, WBSCR14, previously reported in a truncated form as WS-bHLH. The WBSCR14 cDNA encodes an 852amino acid protein with a basic helix-loop-helix-leucine-zipper motif (bHLHZip) and a bipartite nuclear localisation signal (BNLS), suggesting a function as a transcription factor. WBSCR14 is expressed as a 4.2kb transcript predominantly in adult liver and at late stages of foetal development. The WBSCR14 locus encompasses 33 kb of genomic DNA with 17 exons. Two intragenic polymorphic dinucleotide repeats have been identified and used to verify hemizygosity in WBS patients. We have also cloned the mouse ortholog and mapped its locus to mouse chromosome 5, in a region of conserved synteny with human 7q11.23. Given that other bHLHZip proteins are dosage sensitive and based on the putative function of WBSCR14 as a transcription factor, hemizygosity at this locus could be involved in some features of WBS.

de Luis O ，Valero MC ，Jurado LA 《EUROPEAN JOURNAL OF HUMAN GENETICS》

Identification of a putative transcription factor gene (WBSCR11) that is commonly deleted in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a complex developmental disorder involving the hemizygous deletion of genes on chromosome 7q11.23. The cardiovascular aspects of the disorder are known to be caused by haploinsufficiency for ELN, but the genes contributing to the other features of WBS are still undetermined. Fifteen genes have been shown to reside within the WBS deletion, and here we report the identification and cloning of an additional gene that is commonly deleted. WBSCR11, which was identified through genomic DNA sequence analysis and cDNA library screening, was positioned toward the telomeric end of the WBS deletion. The gene is expressed in all adult tissues analyzed, including many regions of the brain. The predicted protein displays homology to another gene from the WBS deletion, GTF2I, which is known to be a transcription factor. We postulate that WBSCR11 is also a transcription factor and may contribute to the spectrum of developmental symptoms found in WBS.

Osborne LR ，Campbell T ，Daradich A ，Scherer SW ，Tsui LC ... -  《GENOMICS》

WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network.

Williams-Beuren syndrome (WBS) is a developmental disorder associated with haploinsufficiency of multiple genes at 7q11.23. Here, we report the functional characterization of WBS critical region gene 14 (WBSCR14), a gene contained in the WBS commonly deleted region. It encodes a basic-helix--loop--helix leucine zipper (bHLHZip) transcription factor of the Myc/Max/Mad superfamily. WBSCR14 is expressed in multiple tissues, including regions of the brain and the intestinal tract. WBSCR14 forms heterodimers with the bHLHZip protein Mlx to bind the DNA sequence CACGTG. Like Max, Mlx has no intrinsic transcriptional activity, but its association with Mad1, Mad4, Mnt or WBSCR14 can repress E-box-dependent transcription. Preliminary results suggest a possible role of WBSCR14 in growth control. Our data support the view that the Max-like bHLHZip protein, Mlx, is a key element of a transcription factor network. We thus suggest that WBSCR14 may contribute to some aspects of the WBS pathology.

Cairo S ，Merla G ，Urbinati F ，Ballabio A ，Reymond A ... -  《HUMAN MOLECULAR GENETICS》

Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a developmental disorder with characteristic physical, cognitive and behavioural traits caused by a microdeletion of approximately 1.5 Mb on chromosome 7q11.23. In total, 24 genes have been described within the deleted region to date. We have isolated and characterised a novel human gene, GTF2IRD2, mapping to the WBS critical region thought to harbour genes important for the cognitive aspects of the disorder. GTF2IRD2 is the third member of the novel TFII-I family of genes clustered on 7q11.23. The GTF2IRD2 protein contains two putative helix-loop-helix regions (I-repeats) and an unusual C-terminal CHARLIE8 transposon-like domain, thought to have arisen as a consequence of the random insertion of a transposable element generating a functional fusion gene. The retention of a number of conserved transposase-associated motifs within the protein suggests that the CHARLIE8-like region may still have some degree of transposase functionality that could influence the stability of the region in a mechanism similar to that proposed for Charcot-Marie-Tooth neuropathy type 1A. GTF2IRD2 is highly conserved in mammals and the mouse ortholgue (Gtf2ird2) has also been isolated and maps to the syntenic WBS region on mouse chromosome 5G. Deletion mapping studies using somatic cell hybrids show that some WBS patients are hemizygous for this gene, suggesting that it could play a role in the pathogenesis of the disorder.

Tipney HJ ，Hinsley TA ，Brass A ，Metcalfe K ，Donnai D ，Tassabehji M ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

Fine-scale comparative mapping of the human 7q11.23 region and the orthologous region on mouse chromosome 5G: the low-copy repeats that flank the Williams-Beuren syndrome deletion arose at breakpoint sites of an evolutionary inversion(s).

Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes deleted in chromosome band 7q11.23. A common deletion including at least 16-17 genes has been defined in the great majority of patients. We have completed a physical and transcription map of the WBS region based on analysis of high-throughput genome sequence data and assembly of a BAC/PAC/YAC contig, including the characterization of large blocks of gene-containing low-copy-number repeat elements that flank the commonly deleted interval. The WBS deletions arise as a consequence of unequal crossing over between these highly homologous sequences, which confer susceptibility to local chromosome rearrangements. We have also completed a clone contig, genetic, and long-range restriction map of the mouse homologous region, including the orthologues of all identified genes in the human map. The order of the intradeletion genes appears to be conserved in mouse, and no low-copy-number repeats are found in the region. However, the deletion region is inverted relative to the human map, exactly at the flanking regions. Thus, we have identified an evolutionary inversion with chromosomal breakpoints at the sites where the human 7q11.23 low-copy-number repeats are located. Additional comparative mapping suggests a model for human chromosome 7 evolution due to serial inversions leading to genomic duplications. This high-resolution mouse map provides the framework required for the generation of mouse models for WBS mimicking the human molecular defect.

Valero MC ，de Luis O ，Cruces J ，Pérez Jurado LA ... -  《GENOMICS》