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1.  Microdeletion at 4q21.3 is associated with intellectual disability, dysmorphic facies, hypotonia, and short stature 
Chromosomal imbalances are a major cause of intellectual disability (ID) and multiple congenital anomalies. We have clinically and molecularly characterized two patients with chromosome translocations and ID. Using whole genome array CGH analysis, we identified a microdeletion involving 4q21.3, unrelated to the translocations in both patients. We confirmed the 4q21.3 microdeletions using fluorescence in situ hybridization and quantitative genomic PCR. The corresponding deletion boundaries in the patients were further mapped and compared to previously reported 4q21 deletions and the associated clinical features. We determined a common region of deletion overlap that appears unique to ID, short stature, hypotonia, and dysmorphic facial features.
PMCID: PMC3325782  PMID: 21834054
Intellectual disability; submicroscopic microdeletion; translocation; hypotonia; short stature; arrayCGH
2.  Evidence that SIZN1 is a Candidate X-Linked Mental Retardation Gene 
An estimated 1-3% of individuals within the United States are diagnosed with mental retardation (MR), yet the cause is unknown in nearly 50% of the patients. While several environmental, genetic and combined teratogenetic etiologies have been identified, many causative genes remain to be identified. Furthermore, the pathogenetic mechanisms underlying MR are known for very few of these genes. Males have a much higher incidence of MR implicating genes on the X-chromosome. We have recently identified a novel gene, SIZN1, on the X-chromosome and showed that it functions in modulating the BMP signaling pathway. Furthermore, we have shown this gene is necessary for basal forebrain cholinergic neuron (BFCN) specific gene expression. Given that cognitive function is impaired when BFCNs are lost or functionally disrupted, we undertook a screen of cognitively impaired males for SIZN1 mutations. We report on four different sequence variants in SIZN1 in 11 individuals with nonsyndromic X-linked mental retardation. Our data implicate SIZN1 as a candidate gene for X-linked mental retardation and/or as a neurocognitive functional modifier.
PMCID: PMC2575800  PMID: 18798319
BMP; SIZN1(ZCCHC12); forebrain cholinergic neuron; X-linked mental retardation
3.  Identification of ectodysplasin-A receptor gene deletion at 2q12.2 and a potential autosomal MR locus 
Mental Retardation (MR) is not a common feature observed in patients with classical ectodermal dysplasias (EDs). Several genes responsible for ectodermal dysplasias and MR have been identified. However, the causation has yet to be identified in a significant number of patients with either ED or MR. Here we have molecularly characterized a de novo balanced translocation t(1;6)(p22.1;p22.1) in a female patient who had mild features of ectodermal dysplasia with hypodontia, microcephaly and cognitive impairment. Mapping of the translocation breakpoints in the patient revealed no obvious causative gene for either ED or MR. Whole genome array CGH analysis unveiled two novel submicroscopic deletions at 2q12.2 and 6q22.3, unrelated to the translocation in the patient. The 2q12.2 deletion contains a known ectodermal dysplasia gene, ectodysplasin-A receptor (EDAR), and the loss of one copy of this gene is considered to be responsible for the ectodermal phenotype in the patient. It is plausible that a potential autosomal MR gene deleted at 2q12.2 or 6q22.3 is likely the cause of the neurodevelopmental defects in the patient.
PMCID: PMC2605173  PMID: 18854857
Mental retardation; ectodermal dysplasia; translocation; arrayCGH; EDAR
5.  Intellectual Disability and Autism Spectrum Disorders: Causal Genes and Molecular Mechanisms 
Intellectual disability (ID) and Autism Spectrum disorder (ASD) are the most common developmental disorders present in humans. Combined, they affect between 3-5% of the population. Additionally, they can be found together in the same individual thereby complicating treatment.
The causative factors (genes, epigenetic and environmental) are quite varied and likely interact so as to further complicate the assessment of an individual patient. Nonetheless, much valuable information has been gained by identifying candidate genes for ID or ASD. Understanding the etiology of either ID or ASD is of utmost importance for families. It allows a determination of the risk of recurrence, the possibility of other comorbidity medical problems, the molecular and cellular nature of the pathobiology and hopefully potential therapeutic approaches.
PMCID: PMC4185273  PMID: 24709068
Intellectual Disability; Autism Spectrum Disorders; Synaptic plasticity; Neurodevelopmental disorder; Molecular pathways
6.  Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome 
Smith–Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS.
PMCID: PMC3260931  PMID: 21897445
Smith–Magenis syndrome; 17p11.2; RAI1; arrayCGH; mutation; deletion
7.  Determinants of Utilization of Antenatal Care Services in Rural Lucknow, India 
Antenatal care services are the first steps towards ensuring the health of mothers and the newborn. This is the key component for achieving Millennium Development Goals by 2015. But India's performance continues to be poor in providing antenatal care services to its huge population, particularly in the rural areas.
To assess the determinants of utilization of antenatal services by rural beneficiaries in Lucknow, a district of north India.
Materials and Methods:
The study, cross-sectional in design, was conducted from August 2009 to July 2010. Multistage random sampling was used for selecting villages. A total of 352 recently delivered women were selected following systematic random sampling. Logistic regression was used to find out the determinants of three antenatal care services.
Overall, 85.5% of the beneficiaries surveyed were found to receive at least three antenatal care services from any health facility. Community health centre was the most common source for such care. Significant difference was found between beneficiaries who took three antenatal care visits and who did not in terms of age, socio economic status, and timing of registration. On multiple regression, only age (OR = 2.107, 95% CI = 1.132 – 3.923) and timing of registration (OR = 2.817, 95% CI = 1.487 – 5.338) were found to be the predictors for three antenatal care visits.
Intervention should be focused on young and late registered women for ensuring sufficient care during pregnancy.
PMCID: PMC3894022  PMID: 24479045
Antenatal care; determinant; recently delivered women; rural India
8.  RAI1 Transcription Factor Activity Is Impaired in Mutants Associated with Smith-Magenis Syndrome 
PLoS ONE  2012;7(9):e45155.
Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
PMCID: PMC3445574  PMID: 23028815
9.  Structural Assessment of the Effects of Amino Acid Substitutions on Protein Stability and Protein-Protein Interaction 
A structure-based approach is described for predicting the effects of amino acid substitutions on protein function. Structures were predicted using a homology modelling method. Folding and binding energy differences between wild-type and mutant structures were computed to quantitatively assess the effects of amino acid substitutions on protein stability and protein–protein interaction, respectively. We demonstrated that pathogenic mutations at the interaction interface could affect binding energy and destabilise protein complex, whereas mutations at the non-interface might reduce folding energy and destabilise monomer structure. The results suggest that the structure-based analysis can provide useful information for understanding the molecular mechanisms of diseases.
PMCID: PMC3319068  PMID: 21297231
Amino acid substitutions; homology modeling; folding energy; binding energy; protein stability; protein-protein interaction
10.  Candidate Agtr2 influenced genes and pathways identified by expression profiling in the developing brain of Agtr2−/y mice 
Genomics  2009;94(3):188-195.
Intellectual disability (ID) is a common developmental disability observed in one to three percent of the human population. A possible role for the Angiotensin II type 2 receptor (AGTR2) in brain function, affecting learning, memory, and behavior, has been suggested in humans and rodents. Mice lacking the Agtr2 gene (Agtr2−/y) showed significant impairment in their spatial memory and exhibited abnormal dendritic spine morphology. To identify Agtr2 influenced genes and pathways, we performed whole genome microarray analysis on RNA isolated from brains of Agtr2−/y and control male mice at embryonic day 15 (E15) and postnatal day one (P1). The gene expression profiles of the Agtr2−/y brain samples were significantly different when compared to profiles of the age-matched control brains. We identified 62 differently expressed genes (p ≤ 0.005) at E15 and in P1 brains of the Agtr2−/y mice. We verified the differential expression of several of these genes in brain samples using quantitative RT-PCR. Differentially expressed genes encode molecules involved in multiple cellular processes including microtubule functions associated with dendritic spine morphology. This study provides insight into Agtr2 influenced candidate genes and suggests that expression dysregulation of these genes may modulate Agtr2 actions in the brain that influences learning and memory.
PMCID: PMC3164574  PMID: 19501643
Learning and memory; Intellectual Disability; Dendritic spine; Expression profiling; Agtr2
11.  Microarray data integration for genome-wide analysis of human tissue-selective gene expression 
BMC Genomics  2010;11(Suppl 2):S15.
Microarray gene expression data are accumulating in public databases. The expression profiles contain valuable information for understanding human gene expression patterns. However, the effective use of public microarray data requires integrating the expression profiles from heterogeneous sources.
In this study, we have compiled a compendium of microarray expression profiles of various human tissue samples. The microarray raw data generated in different research laboratories have been obtained and combined into a single dataset after data normalization and transformation. To demonstrate the usefulness of the integrated microarray data for studying human gene expression patterns, we have analyzed the dataset to identify potential tissue-selective genes. A new method has been proposed for genome-wide identification of tissue-selective gene targets using both microarray intensity values and detection calls. The candidate genes for brain, liver and testis-selective expression have been examined, and the results suggest that our approach can select some interesting gene targets for further experimental studies.
A computational approach has been developed in this study for combining microarray expression profiles from heterogeneous sources. The integrated microarray data can be used to investigate tissue-selective expression patterns of human genes.
PMCID: PMC2975411  PMID: 21047382
12.  Sequence feature-based prediction of protein stability changes upon amino acid substitutions 
BMC Genomics  2010;11(Suppl 2):S5.
Protein destabilization is a common mechanism by which amino acid substitutions cause human diseases. Although several machine learning methods have been reported for predicting protein stability changes upon amino acid substitutions, the previous studies did not utilize relevant sequence features representing biological knowledge for classifier construction.
In this study, a new machine learning method has been developed for sequence feature-based prediction of protein stability changes upon amino acid substitutions. Support vector machines were trained with data from experimental studies on the free energy change of protein stability upon mutations. To construct accurate classifiers, twenty sequence features were examined for input vector encoding. It was shown that classifier performance varied significantly by using different sequence features. The most accurate classifier in this study was constructed using a combination of six sequence features. This classifier achieved an overall accuracy of 84.59% with 70.29% sensitivity and 90.98% specificity.
Relevant sequence features can be used to accurately predict protein stability changes upon amino acid substitutions. Predictive results at this level of accuracy may provide useful information to distinguish between deleterious and tolerant alterations in disease candidate genes. To make the classifier accessible to the genetics research community, we have developed a new web server, called MuStab (
PMCID: PMC2975416  PMID: 21047386
13.  A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation 
Tarpey, Patrick S | Smith, Raffaella | Pleasance, Erin | Whibley, Annabel | Edkins, Sarah | Hardy, Claire | O'Meara, Sarah | Latimer, Calli | Dicks, Ed | Menzies, Andrew | Stephens, Phil | Blow, Matt | Greenman, Chris | Xue, Yali | Tyler-Smith, Chris | Thompson, Deborah | Gray, Kristian | Andrews, Jenny | Barthorpe, Syd | Buck, Gemma | Cole, Jennifer | Dunmore, Rebecca | Jones, David | Maddison, Mark | Mironenko, Tatiana | Turner, Rachel | Turrell, Kelly | Varian, Jennifer | West, Sofie | Widaa, Sara | Wray, Paul | Teague, Jon | Butler, Adam | Jenkinson, Andrew | Jia, Mingming | Richardson, David | Shepherd, Rebecca | Wooster, Richard | Tejada, M Isabel | Martinez, Francisco | Carvill, Gemma | Goliath, Rene | de Brouwer, Arjan P M | van Bokhoven, Hans | Van Esch, Hilde | Chelly, Jamel | Raynaud, Martine | Ropers, Hans-Hilger | Abidi, Fatima E | Srivastava, Anand K | Cox, James | Luo, Ying | Mallya, Uma | Moon, Jenny | Parnau, Josef | Mohammed, Shehla | Tolmie, John L | Shoubridge, Cheryl | Corbett, Mark | Gardner, Alison | Haan, Eric | Rujirabanjerd, Sinitdhorn | Shaw, Marie | Vandeleur, Lucianne | Fullston, Tod | Easton, Douglas F | Boyle, Jackie | Partington, Michael | Hackett, Anna | Field, Michael | Skinner, Cindy | Stevenson, Roger E | Bobrow, Martin | Turner, Gillian | Schwartz, Charles E | Gecz, Jozef | Raymond, F Lucy | Futreal, P Andrew | Stratton, Michael R
Nature genetics  2009;41(5):535-543.
Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
PMCID: PMC2872007  PMID: 19377476
14.  Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation 
Nature genetics  2007;39(9):1127-1133.
Nonsense-mediated mRNA decay (NMD) is of universal biological significance1-3. It has emerged as an important global RNA, DNA and translation regulatory pathway4. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype5,6 and one with the FG phenotype7. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery8,9. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.
PMCID: PMC2872770  PMID: 17704778
15.  Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities 
Genomics  2007;91(2):195-202.
We have identified disruptions of the dedicator of cytokinesis 8 gene, DOCK8, in two unrelated patients with mental retardation. In one patient, a male with MR and no speech, we mapped a genomic deletion of approximately 230 kb in subtelomeric 9p. In the second patient, a female with mental retardation and ectodermal dysplasia and a balanced translocation t(X;9)(q13.1;p24), we mapped the 9p24 breakpoint to a region overlapping with the centromeric end of the 230 kb subtelomeric deletion. We characterized the DOCK8 gene from the critical 9p deletion region and determined the longest isoform of the DOCK8 gene is truncated in both patients. Furthermore, the DOCK8 gene is expressed in several human tissues including adult and fetal brain. Recently, a role for DOCK8 in processes that affect organization of filamentous actin has been suggested. Several genes influencing actin cytoskeleton have been implicated in human cognitive function and thus a possibility exists that the rare mutations of the DOCK8 gene may contribute to some cases of autosomal dominant mental retardation.
PMCID: PMC2245991  PMID: 18060736
Subtelomere; Mental retardation; Chromosome translocation; DOCK8; Autosome
16.  Identification of ectodysplasin-A receptor gene deletion at 2q12.2 and a potential autosomal MR locus 
Mental retardation (MR) is not a common feature observed in patients with classical ectodermal dysplasias (EDs). Several genes responsible for EDs and MR have been identified. However, the causation has yet to be identified in a significant number of patients with either ED or MR. Here, we have molecularly characterized a de novo balanced translocation t(1;6)(p22.1;p22.1) in a female patient who had mild features of ED with hypodontia, microcephaly, and cognitive impairment. Mapping of the translocation breakpoints in the patient revealed no obvious causative gene for either ED or MR. Whole genome array CGH analysis unveiled two novel submicroscopic deletions at 2q12.2 and 6q22.3, unrelated to the translocation in the patient. The 2q12.2 deletion contains a known ED gene, ectodysplasin-A receptor (EDAR), and the loss of one copy of this gene is considered to be responsible for the ectodermal phenotype in the patient. It is plausible that a potential autosomal MR gene deleted at 2q12.2 or 6q22.3 is likely the cause of the neurodevelopmental defects in the patient.
PMCID: PMC2605173  PMID: 18854857
mental retardation; ectodermal dysplasia; translocation; arrayCGH; EDAR
17.  tSNP-based identification of allelic-loss of gene expression in a patient with a balanced chromosomal rearrangement 
Genomics  2007;89(4):562-565.
Identification of genes affected by disease-associated rare chromosomal rearrangements has led to cloning of several disease genes. Here we have used a simple approach involving allele-specific RT-PCR-based detection of gene expression to identify a gene affected by a balanced autosome;autosome translocation. We identified a transcribed SNP (tSNP), c.68G>A, present in a novel untranslated exon of the CLDN14 gene in a male patient with mental retardation (MR) who had a balanced t(13;21) chromosomal translocation. We determined an allelic-loss of expression of the CLDN14 gene isoform at the 21q22.1 chromosomal breakpoint. Although additional work is necessary to explore a possible function of the novel CLDN14 isoform in brain development and function and the potential pathogenic consequences of its disruption in this patient, the result clearly demonstrates the utility of a tSNP-based detection of allelic-loss of gene expression in studies involving chromosomal rearrangements.
PMCID: PMC1880898  PMID: 17241765
Chromosome translocation; tSNP; RT-PCR; Allele-specific expression
18.  Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption 
Nature genetics  2001;27(1):79-83.
The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body’s ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250–500 mg of dietary cholesterol and about 200–400 mg of non-cholesterol sterols. About 50–60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine1,2. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease3. We previously mapped the STSL locus to human chromosome 2p21 (ref. 4) and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.
PMCID: PMC1350991  PMID: 11138003

Results 1-18 (18)