Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development

The gene GTF2IRD1 is localized within the critical region on chromosome 7 that is deleted in Williams syndrome patients. Genotype-phenotype comparisons of patients carrying variable deletions within this region have implicated GTF2IRD1 and a closely related homolog, GTF2I, as prime candidates for the causation of the principal symptoms of Williams syndrome. We have generated mice with an nls-LacZ knockin mutation of the Gtf2ird1 allele to study its functional role and examine its expression profile. In adults, expression is most prominent in neurons of the central and peripheral nervous system, the retina of the eye, the olfactory epithelium, the spiral ganglion of the cochlea, brown fat adipocytes and to a lesser degree myocytes of the heart and smooth muscle. During development, a dynamic pattern of expression is found predominantly in musculoskeletal tissues, the pituitary, craniofacial tissues, the eyes and tooth buds. Expression of Gtf2ird1 in these tissues correlates with the manifestation of some of the clinical features of Williams syndrome.     

Mapping Genetically Controlled Neural Circuits of Social Behavior and Visuo-Motor Integration by a Preliminary Examination of Atypical Deletions with Williams Syndrome

In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.     

Williams-Beuren syndrome: a model of recurrent genomic mutation

Williams-Beuren syndrome is a segmental aneusomy syndrome with manifestations affecting the vascular, connective tissue, endocrine and central nervous systems. Most patients show a similar heterozygous approximately 1.5 Mb deletion at 7q11.23 that contains a number of reported genes. Deletion mapping in the few atypical patients with smaller deletions suggested that additive effects of haploinsufficiency for two or more genes might be necessary for the phenotype. Vascular stenoses are caused by haploinsufficiency at the elastin gene, while the genes responsible for the cognitive deficits are likely located at the telomeric edge of the deletion, including CYLN2 and GTF2I. Large region-specific segmental duplications predispose to misalignment and inter- or intrachromosomal unequal crossing-over causing the deletions. Atypical alleles at 7q11.23 such as inversions and deletions/insertions of large repeats, also generated through aberrant recombination between the local segmental duplications, are found in approximately 35% of transmitting parents. Genomic instability at 7q11.23 is directly related to the genomic structure of the region.     

Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension

Williams-Beuren syndrome (WBS), caused by a heterozygous deletion at 7q11.23, represents a model for studying hypertension, the leading risk factor for mortality worldwide, in a genetically determined disorder. Haploinsufficiency at the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, present in approximately 50% of patients. Detailed clinical and molecular characterization of 96 patients with WBS was performed to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and were found to result in variability at two genes, NCF1 and GTF2IRD2. Hypertension was significantly less prevalent in patients with WBS who had the deletion that included NCF1 (P=.02), a gene coding for the p47(phox) subunit of the NADPH oxidase. Decreased p47(phox) protein levels, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. Our results indicate that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II-mediated oxidative stress. Therefore, antioxidant therapy that reduces NADPH oxidase activity might have a potential benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism.     

Complex Study of Drosophila Mutants in the agnostic Locus: A Model for Coupling Chromosomal Architecture and Cognitive Functions

After the devastation of genetics in our country, Academician Leon A. Orbeli has provided an opportunity for the studies on evolutionary conservatism of genes controlling the main properties of the higher nervous activity and conditioning. For the last few years, determination and bioinformatic analysis of genome sequences in the plant, worm, Drosophila, and human genome have revealed, indeed, a high interspecies homology of genes. Studies on Drosophila mutants have shown that components of intracellular signalization systems regulating neuronal functions and gene expression are organized in supramolecular complexes. It has become evident that the chromosomal architecture predetermines the appearance of deletions, duplications, insertions, and translocations and, therefore, plays an important role not only in evolution but also in generating human pathological syndromes with multiple manifestations, including cognitive dysfunctions. There appeared a new approach, comparative genomics, that allows revealing functions of human disease genes on the basis of their sequence homology to the known Drosophila gene with various well-studied mutant phenotypes. For this reason, the Drosophila genes should be saturated with mutant phenotypes, and these are to be studied in comparison with the chromosomal architecture. Our complex behavioral and molecular-genetic study of spontaneous, induced, and P-insertional mutations in the Drosophila agnostic locus and the bioinformatic analyses of genomic sequences has allowed us to assign the locus to the Drosophila genomic scaffold AE003489 from the 11AB X-chromosomal region that contains the CG1848 gene coding for LIM-kinase 1. Mutations, insertions, and deletions in the agnostic locus lead to an increased activity of Ca²⁺/calmodulin-dependent PDE1, resistance to ether, an inactivator of synaptic transmission, impairments of the brain structures, learning and memory defects in conditioned courtship suppression paradigm, alterations in sound production and in structural-functional chromosomal organization. Therefore, the agnostic locus represents a model to study the human Williams syndrome with multiple dysfunctions due to a contiguous deletion in the 7q11.23 spanning 17 genes, among them the gene for LIM-kinase 1 presumed to be responsible for cognitive defects. The Williams syndrome is considered to be a most efficient model to study human cognition, human genome organization, and evolution.