TFII-I gene family during tooth development: candidate genes for tooth anomalies in Williams syndrome.

Williams syndrome is a rare congenital disorder involving the cardiovascular system, mental retardation, distinctive facial features, and tooth anomalies. It is caused by the heterozygous deletion of approximately 1.6 Mb encompassing 28 genes on human chromosome 7q11.23. It has been suggested that the genes responsible for craniofacial anomalies are located in the telomeric end region, which harbors three members of the TFII-I gene family (Tassabehji et al. [2005] Science 310:1184). To recognize potential candidate genes for the tooth anomalies in Williams syndrome, we carried out comparative in situ hybridization analysis of members of TFII-I gene family during murine odontogenesis. Gtf2i showed widespread expression in the developing head but was higher in the developing teeth than surrounding tissues throughout tooth development. At the bud stage, Gtf2ird1 and Gtf2ird2 were expressed in the epithelial buds. At the early bell stage, expression of Gtf2ird1 and Gtf2ird2 was observed in preameloblasts and preodontoblasts.     

Defining the social phenotype in Williams syndrome: a model for linking gene, the brain, and behavior

Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology.     

BAZ1B is a candidate gene responsible for hypothyroidism in Williams syndrome

Williams syndrome (WS) is a rare neurodevelopmental disorder associated to a hemizygous deletion of 28 genes located on chromosome 7q11.23. WS affected subjects frequently suffer from several endocrine abnormalities including hypothyroidism due to defects in thyroid morphology. To date, several genes involved in thyroid dysgenesis have been identified, nonetheless, none of them is located in the 7q11.23 region. Thus, the hypothyroidism-linked molecular features in WS are not yet known. In this study we focused on one of the WS deleted gene, BAZ1B, demonstrating that its downregulation in thyroid cells leads to cell viability and survival decrement. Taking together, our results show that BAZ1B could be the mainly responsible for thyroid defects observed in some of WS patients and that these alterations are activated by PTEN-mediated mechanisms.     

Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome

The human gene HIC1 (hypermethylated in cancer) maps to chromosome 17p13.3 and is deleted in the contiguous gene disorder Miller-Dieker syndrome (MDS) [Makos-Wales et al. (1995) Nature Med., 1, 570-577; Chong et al. (1996) Genome Res., 6, 735-741]. We isolated the murine homologue Hic1, encoding a zinc-finger protein with a poxvirus and zinc-finger (POZ) domain and mapped it to mouse chromosome 11 in a region exhibiting conserved synteny to human chromosome 17. Comparison of genomic and cDNA sequences predicts two exons for the murine Hic1. The second exon exhibits 88% identity to the human HIC1 on DNA level. During embryonic development, Hic1 is expressed in mesenchymes of the sclerotomes, lateral body wall, limb and cranio-facial regions embedding the outgrowing peripheral nerves during their differentiation. During fetal development, Hic1 additionally is expressed in mesenchymes apposed to precartilaginous condensations, at many interfaces to budding epithelia of inner organs, and weakly in muscles. We observed activation of Hic1 expression in the embryonic anlagen of many tissues displaying anomalies in MDS patients. Besides lissencephaly, MDS patients exhibit facial dysmorphism and frequently additional birth defects, e.g. anomalies of the heart, kidney, gastrointestinal tract and the limbs (OMIM 247200). Thus, HIC1 activity may correlate with the defective development of the nose, jaws, extremities, gastrointestinal tract and kidney in MDS patients.     

Preliminary evidence for a cognitive phenotype in Barth syndrome

Barth syndrome (BTHS) is a rare, X-linked, recessive disorder that affects almost exclusively males. It is characterized by short stature, cardioskeletal myopathy, cyclic neutropenia, increased excretion of 3-methylglutaconic acid in the urine, and moderate hypocholesterolemia. The objective of the present study was to assess whether BTHS presents with a cognitive phenotype. Preliminary data were collected from five kindergarten or first-grade boys with BTHS. An abbreviated psychoeducational test battery was administered to each boy, and parents of each boy completed standardized behavior rating scales. Data from 120 boys of similar age or grade level were used for one comparison group; a subset of this sample comprised a comparison group that was individually matched on age and grade level to one of the five boys with BTHS. Preliminary data reflect a higher incidence of cognitive difficulties in boys with BTHS relative to both comparison groups. Boys with BTHS had significantly lower visual spatial skills, but comparable reading-related skills, when compared with either group. Although based on a small sample size, the preliminary data presented in this work are the first indication of a cognitive phenotype associated with BTHS.     

Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development

Velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of abnormalities, including conotruncal heart defects, velopharyngeal insufficiency, craniofacial anomalies and learning disabilities. In addition, numerous other clinical features have been described, including frequent psychiatric illness. Hemizygosity for a 1.5-3 Mb region of chromosome 22q11 has been detected in >80% of VCFS/DGS patients. It is thought that a developmental field defect is responsible for many of the abnormalities seen in these patients and that the defect occurs due to reduced levels of a gene product active in early embryonic development. Goosecoid-like ( GSCL ) is a homeobox gene which is present in the VCFS/DGS commonly deleted region. The mouse homolog, Gscl, is expressed in mouse embryos as early as E8.5. Gscl is related to Goosecoid ( Gsc ), a gene required for proper craniofacial development in mice. GSCL has been considered an excellent candidate for contributing to the developmental defects in VCFS/DGS patients. To investigate the role of Goosecoid-like in VCFS/DGS etiology, we disrupted the Gscl gene in mouse embryonic stem cells and produced mice that transmit the disrupted allele. Mice that are homozygous for the disrupted allele appear to be normal and they do not exhibit any of the anatomical abnormalities seen in VCFS/DGS patients. RNA in situ hybridization to mouse embryo sections revealed that Gscl is expressed at E8.5 in the rostral region of the foregut and at E11.5 and E12.5 in the developing brain, in the pons region and in the choroid plexus of the fourth ventricle. Although the gene inactivation experiments indicate that haploinsufficiency for GSCL is unlikely to be the sole cause of the developmental field defect thought to be responsible for many of the abnormalities in VCFS/DGS patients, its localized expression during development could suggest that hemizygosity for GSCL, in combination with hemizygosity for other genes in 22q11, contributes to some of the developmental defects as well as the behavioral anomalies seen in these patients. The mice generated in this study should help in evaluating these possibilities.      

A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene

The identification of mouse models for the various forms ofhuman neurosensory non-syndromic recessive deafness would constitutea major advance in the study of human deafness. Here we describethe localization of a human gene for neurosensory, non-syndromicrecessive deafness (NSRD2) to chromosome 11q13.5 by linkageanalysis of a highly consanguineous family. A maximum lod scoreof 10.63 (     

Dethroning the myth: cognitive dissociations and innate modularity in Williams syndrome

Despite increasing empirical data to the contrary, it continues to be claimed that mor-phosyntax and face processing skills of people with Williams syndrome are intact. This purported intactness, which coexists with mental retardation, is used to bolster claims about innately specified, independently functioning modules, as if the atypically developing brain were simply a normal brain with parts intact and parts impaired. Yet this is highly unlikely, given the dynamics of brain development and the fact that in a genetic microdeletion syndrome the brain is developing differently from the moment of conception, throughout embryogenesis, and during postnatal brain growth. In this article, we challenge the intactness assumptions, using evidence from a wide variety of studies of toddlers, children, and adults with Williams syndrome.     

The methylator phenotype in microsatellite stable colorectal cancers is characterized by a distinct gene expression profile

The CpG island methylator phenotype (CIMP) in colorectal tumours can be recognized by an increased frequency of aberrant methylation in a specific set of genomic loci. Because of the strong association of CIMP with high microsatellite instability (MSI-H), the identification of CIMP+ tumours within microsatellite stable (MSS) colorectal cancers may not be straightforward. To overcome this potential limitation, we have built an improved seven-locus set of methylation markers that includes CACNA1G, IGF2, RUNX3, HTR6, RIZ1, MINT31, and MAP1B. This new set of CIMP markers revealed a bimodal distribution of methylation frequencies in a group of 95 MSS colorectal cancers, which allowed a clearer separation between CIMP classes. Correlation of MSS CIMP+ tumours with bio-pathological traits revealed significant associations with location to the proximal colon, mucinous histology, BRAF mutation, and chromosomal stability. A potential trend towards an adverse prognosis of CIMP+ cases was associated with the high frequency of BRAF mutations present within this cohort of tumours. Microarray analysis revealed that CIMP+ tumours are characterized by a unique expression profile, a result that confirms that CIMP+ tumours represent a truly distinct molecular class within MSS colorectal cancers.     

Blepharophimosis plus ovarian failure: a likely candidate for a contiguous gene syndrome.

We describe four females from three families with blepharophimosis, epicanthus inversus, and ptosis who were found to have premature ovarian failure. In two families the inheritance was autosomal dominant and in one it was a new mutation. Two females had, in addition, dysmorphic facial features which have been described in other cases. We suggest that the aetiology of the blepharophimosis ovarian failure syndrome is a contiguous gene syndrome.     

The spinal precerebellar nuclei: Calcium binding proteins and gene expression profile in the mouse

We have localized the spinocerebellar neuron groups in C57BL/6J mice by injecting the retrograde neuronal tracer Fluoro-Gold into the cerebellum and examined the distribution of SMI 32 and the calcium-binding proteins (CBPs), calbindin-D-28K (Cb), calretinin (Cr), and parvalbumin (Pv) in the spinal precerebellar nuclei. The spinal precerebellar neuron clusters identified were the dorsal nucleus, central cervical nucleus, lumbar border precerebellar nucleus, lumbar precerebellar nucleus, and sacral precerebellar nucleus. Some dispersed neurons in the deep dorsal horn and spinal laminae 6–8 also projected to the cerebellum. Cb, Cr, Pv, and SMI 32 were present in all major spinal precerebellar nuclei and Pv was the most commonly observed CBP. A number of genes expressed in hindbrain precerebellar nuclei are also expressed in spinal precerebellar groups, but there were some differences in gene expression profile between the different spinal precerebellar nuclei, pointing to functional diversity amongst them.     

JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype

Alagille syndrome (AGS, MIM 118450) is an autosomal dominant disorder with a variable phenotype characterised by hepatic, eye, cardiac, and skeletal malformations and a characteristic facial appearance. Mutations within the gene JAGGED1 (JAG1), which encodes a ligand for NOTCH receptor(s), has been shown to cause Alagille syndrome. Interactions of NOTCH receptors and their ligands influence cell fate decisions in several developmental pathways. We report the tissue expression of JAG1 in human embryos.
We have performed tissue in situ hybridisation on human embryos aged 32-52 days using ³⁵S labelled riboprobes for JAG1. JAG1 is expressed in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube. We conclude that JAG1 is expressed in the structures affected in Alagille syndrome, such as the pulmonary artery, anterior chamber of the eye, and face.


Keywords: Alagille syndrome; arteriohepatic dysplasia; JAGGED1; NOTCH signalling