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The B-box family is an expanding new family of genes encoding proteins involved in diverse cellular functions such as developmental patterning and oncogenesis. A member of this protein family, MID1, is the gene responsible for the X-linked form of Opitz G/BBB syndrome, a developmental disorder characterized by defects of the midline structures. We now report the identification of MID2, a new transcript closely related to MID1. MID2 maps to Xq22 in human and to the syntenic region on the mouse X chromosome. The two X-linked genes share the same domains, the same exon-intron organization, a high degree of similarity at the protein level and the same subcellular localization, both being confined to the cytoplasm in association to micro-tubular structures. The expression pattern studied by RNA in situ hybridization in mouse revealed that Mid2 is expressed early in development and the highest level of expression is detected in the heart, unlike Mid1 for which no expression was detected in the developing heart. Together, these data suggest that midin and MID2 have a similar biochemical function but a different physiological role during development.
Hum Mol Genet 1999 Aug
PMID:MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development. 1040 Sep 86

Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.
Mol Genet Metab 2000 Mar
PMID:An unexpected affected female patient in a classical Lesch-Nyhan family. 1076 82

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.
Hum Mol Genet 2001 Mar 15
PMID:WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. 1123 Jan 81

Ke 6 is a 17beta-hydroxysteroid dehydrogenase (17betaHSD) that is expressed in the kidneys and gonads. The expression of this gene is markedly reduced in three murine models of recessive polycystic kidney disease, a developmental disorder, where some nephrons within the affected kidneys develop into huge fluid-filled cysts while the non-cystic nephrons atrophies by apoptosis. Here, we show that in the cpk/cpk mouse, which have polycystic kidneys, the female reproductive organs also fail to mature properly and remain arrested at an early stage of development. Direct measurement of 17betaHSD activity showed a severe reduction in estrogen and androgen metabolism within gonadal and non-gonadal tissues of the cpk/cpk mouse. Using immunofluorescent staining we localized the expression of the Ke 6 protein within the female mouse reproductive organs. Our findings suggest that estrogen/androgen metabolism may play an important role in the development of the urogenital systems.
Mol Cell Endocrinol 2001 May 15
PMID:Immature ovaries and polycystic kidneys in the congenital polycystic kidney mouse may be due to abnormal sex steroid metabolism. 1136 55

Alagille syndrome is a human autosomal dominant developmental disorder characterized by liver, heart, eye, skeletal, craniofacial and kidney abnormalities. Alagille syndrome is caused by mutations in the Jagged 1 (JAG1) gene, which encodes a ligand for Notch family receptors. The majority of JAG1 mutations seen in Alagille syndrome patients are null alleles, suggesting JAG1 haploinsufficiency as a primary cause of this disorder. Mice homozygous for a Jag1 null mutation die during embryogenesis and Jag1/+ heterozygous mice exhibit eye defects but do not exhibit other phenotypes characteristic of Alagille syndrome patients ( Xue, Y., Gao, X., Lindsell, C. E., Norton, C. R., Chang, B., Hicks, C., Gendron-Maguire, M., Rand, E. B., Weinmaster, G. and Gridley, T. (1999) HUM: Mol. Genet. 8, 723-730). Here we report that mice doubly heterozygous for the Jag1 null allele and a Notch2 hypomorphic allele exhibit developmental abnormalities characteristic of Alagille syndrome. Double heterozygous mice exhibit jaundice, growth retardation, impaired differentiation of intrahepatic bile ducts and defects in heart, eye and kidney development. The defects in bile duct epithelial cell differentiation and morphogenesis in the double heterozygous mice are similar to defects in epithelial morphogenesis of Notch pathway mutants in Drosophila, suggesting that a role for the Notch signaling pathway in regulating epithelial morphogenesis has been conserved between insects and mammals. This work also demonstrates that the Notch2 and Jag1 mutations interact to create a more representative mouse model of Alagille syndrome and provides a possible explanation of the variable phenotypic expression observed in Alagille syndrome patients.
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PMID:A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. 1186 89

Disruption of one copy of the human CREB binding protein (CBP or CREBBP) gene leads to the Rubinstein-Taybi syndrome (RTS), a developmental disorder characterized by retarded growth and mental functions, broad thumbs, broad big toes and typical facial abnormalities. The CREB binding protein (CBP) is an essential transcriptional coactivator for many different transcription factors. CBP has the intrinsic ability to acetylate histones and other proteins, which is regarded as an important step in transcription activation. In vitro studies have shown that this enzymatic activity critically depends on the integrity of a plant homeodomain (PHD)-type zinc finger in the HAT domain of CBP. We therefore investigated whether PHD finger mutations are present in RTS patients. Mutational analysis of 39 patients revealed eight novel heterozygous mutations in the HAT domain of CBP, one of which alters a conserved PHD finger amino acid (E1278K), while a second mutation deletes exon 22, which encodes the central region of the PHD finger. Functional analysis of these RTS-associated PHD finger mutants showed that they lacked in vitro acetyltransferase activity towards histones and CBP itself and displayed reduced coactivator function for the transcription factor CREB. Importantly, in EBV-transformed lymphoblastoid cells from the exon 22 deletion patient we found approximately 50% less endogenous CBP HAT activity. These findings therefore underscore the functional importance of the PHD finger in vivo and imply that reduction of CBP HAT activity, as exemplified here by disruption of the PHD finger, is sufficient to cause RTS.
Hum Mol Genet 2003 Feb 15
PMID:Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome. 1256 91

Bardet-Biedl syndrome (BBS: OMIM 209900) is a rare developmental disorder that exhibits significant clinical and genetic heterogeneity. Although modeled initially as a purely recessive trait, recent data have unmasked an oligogenic mode of disease transmission, in which mutations at different BBS loci can interact genetically in some families to cause and/or modify the phenotype. Here, I will review and discuss recent advances in elucidating both genetic and cellular aspects of this phenotype and their potential application in understanding the genetic basis of phenotypic variability and oligogenic inheritance.
Hum Mol Genet 2004 Apr 01
PMID:The oligogenic properties of Bardet-Biedl syndrome. 1497 58

Autism is a developmental disorder of unknown aetiopathology and lacking any specific pharmacological therapeutic intervention. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and acetylcholine have been implicated. Abnormalities in nicotinic acetylcholine receptors have been identified including cortical loss of binding to the alpha4/beta2 subtype and increase in cerebellar alpha7 binding. Receptor expression (mRNA) has not so far been systematically examined. This study aims to further explore the role of nicotinic receptors in autism by analysing nicotinic receptor subunit mRNA in conjunction with protein levels and receptor binding in different brain areas. Quantitative RT-PCR for alpha4, alpha7 and beta2 subunit mRNA expression levels; alpha3, alpha4, alpha7 and beta2 subunit protein expression immunochemistry and specific radioligand receptor binding were performed in adult autism and control brain samples from cerebral cortex and cerebellum. Alpha4 and beta2 protein expression and receptor binding density as well as alpha4 mRNA levels were lower in parietal cortex in autism, while alpha7 did not change for any of these parameters. In cerebellum, alpha4 mRNA expression was increased, whereas subunit protein and receptor levels were decreased. Alpha7 receptor binding in cerebellum was increased alongside non-significant elevations in mRNA and protein expression levels. No significant changes were found for beta2 in cerebellum. The data obtained, using complementary measures of receptor expression, indicate that reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum. The findings point to dendritic and/or synaptic nicotinic receptor abnormalities that may relate to disruptions in cerebral circuitry development.
Brain Res Mol Brain Res 2004 Apr 07
PMID:Molecular analysis of nicotinic receptor expression in autism. 1504 69

To date, the only reported genetic defect identified in the developmental disorder, Seckel syndrome, is a mutation in ataxia telangiectasia and Rad3-related protein (ATR). Seckel syndrome is clinically and genetically heterogeneous and whether defects in ATR significantly contribute to Seckel syndrome is unclear. Firstly, we characterize ATR-Seckel cells for their response to DNA damage. ATR-Seckel cells display impaired phosphorylation of ATR-dependent substrates, impaired G2/M checkpoint arrest and elevated micronucleus (MN) formation following exposure to UV and agents that cause replication stalling. We describe a novel phenotype, designated nuclear fragmentation (NF), that occurs following replication arrest. Finally, we report that ATR-Seckel cells have an endogenously increased number of centrosomes in mitotic cells demonstrating a novel role for ATR in regulating centrosome stability. We exploit these phenotypes to examine cell lines derived from additional unrelated Seckel syndrome patients. We show that impaired phosphorylation of ATR-dependent substrates is a common but not invariant feature of Seckel syndrome cell lines. In contrast, all cell lines displayed defective G2/M arrest, increased levels of NF and MN formation following exposure to agents that cause replication stalling. All the Seckel syndrome cell lines examined showed increased endogenous centrosome numbers. Though ATR cDNA can complement the defects in ATR-Seckel cells, it failed to complement any of the additional cell lines. We conclude that Seckel syndrome represents a further damage response disorder that is uniquely associated with defects in the ATR-signalling pathway resulting in failed checkpoint arrest following exposure to replication fork stalling.
Hum Mol Genet 2004 Dec 15
PMID:Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. 1549 23

Dyslexia is a common and complex developmental disorder manifested by unexpected difficulty in learning to read. Multiple different measures are used for diagnosis, and may reflect different biological pathways related to the disorder. Impaired phonological decoding (translation of written words without meaning cues into spoken words) is thought to be a core deficit. We present a genome scan of two continuous measures of phonological decoding ability: phonemic decoding efficiency (PDE) and word attack (WA). PDE measures both accuracy and speed of phonological decoding, whereas WA measures accuracy alone. Multipoint variance component linkage analyses (VC) and Markov chain Monte-Carlo (MCMC) multipoint joint linkage and segregation analyses were performed on 108 families. A strong signal was observed on chromosome 2 for PDE using both VC (LOD=2.65) and MCMC methods (intensity ratio (IR)=32.1). The IR is an estimate of the ratio of the posterior to prior probability of linkage in MCMC analysis. The chromosome 2 signal was not seen for WA. More detailed mapping with additional markers provided statistically significant evidence for linkage of PDE to chromosome 2, with VC-LOD=3.0 and IR=59.6 at D2S1399. Parametric analyses of PDE, using a model obtained by complex segregation analysis, provided a multipoint maximum LOD=2.89. The consistency of results from three analytic approaches provides strong evidence for a locus on chromosome 2 that influences speed but not accuracy of phonological decoding.
Mol Psychiatry 2005 Jul
PMID:A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency. 1575 56


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