ABSTRACT
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.
Subject(s)
Genetics, Medical , Humans , History, 20th Century , History, 21st Century , Human GeneticsABSTRACT
BACKGROUND: Failure to rescue (FTR) is a quality metric defined as mortality after potentially preventable complications after surgery. Predicting patients who are at the highest risk of mortality after a complication may aid in preventing deaths. Thirty-day follow-up period inadequately captures postoperative deaths; alternatively, a 90-day follow-up period has been advocated. This study aimed to examine the association of a validated frailty metric, the risk analysis index (RAI), with 90-day FTR (FTR-90). METHODS: Patients aged ≥65 years who underwent a major abdominal operation between 2014 and 2020 at a quaternary care center were abstracted. Institutional data were merged with the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and Geriatric Surgery Research File variables. The association between RAI and FTR-90 was evaluated using multivariable logistic regression. RESULTS: A total of 398 patients with postoperative complications were included. Fifty-two patients (13.1%) died during the 90-day follow-up. The FTR-90 group was older (median age: 76 vs 73 years, respectively; P = .002), had a greater preoperative American Society of Anesthesiologists classification score (P < .001), and had a higher ACS NSQIP estimated risk of morbidity (0.33% vs 0.20%, P < .001) and mortality (0.067% vs 0.012%, P < .001). The FTR-90 group had a greater median RAI score (23 vs 19; P = .002). The RAI score was independently associated with FTR-90 (odds ratio, 1.04; 95% CI, 1.0042-1.0770; P = .028) but not with FTR-30 (P = .13). CONCLUSION: Preoperative frailty, as defined by RAI, is independently associated with FTR at 90-day follow-up. FTR-90 captured nearly 60% more deaths than did FTR-30. Frailty has major implications beyond the typical 30-day follow-up period, and a longer follow-up period must be considered.
Subject(s)
Frailty , Humans , Aged , Frailty/complications , Abdomen/surgery , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Odds Ratio , Quality ImprovementABSTRACT
Objective: Mitral valve repair is the gold standard for treatment of mitral regurgitation, but the optimal technique remains debated. By using a regional collaborative, we sought to determine the change in repair technique over time. Methods: We identified all patients undergoing isolated mitral valve repair from 2012 to 2022 for degenerative mitral disease. Those with endocarditis, transcatheter repair, or tricuspid intervention were excluded. Continuous variables were analyzed via Wilcoxon rank sum, and categorical variables were analyzed via chi-square testing. Results: We identified 1653 patients who underwent mitral valve repair, with 875 (59.2%) undergoing a no resection repair. Over the last decade, there was no significant trend in the proportion of repair techniques across the region (P = .96). Those undergoing no resection repairs were more likely to have undergone prior cardiac surgery (5.0% vs 2.2%, P = .002) or minimally invasive approaches (61.4% vs 24.7%, P < .001) with similar predicted risk of mortality (median 0.6% vs 0.6%, P = .75). Intraoperatively, no resection repairs were associated with longer bypass times (140 [117-167] minutes vs 122 [91-159] minutes, P < .001). Operative mortality was similar between both groups (1.1% vs 1.0%, P = .82), as were other postoperative outcomes. Anterior leaflet prolapse (odds ratio, 11.16 [6.34-19.65], P < .001) and minimally invasive approach (odds ratio, 6.40 [5.06-8.10], P < .001) were most predictive of no resection repair. Conclusions: Despite minor differences in operative times, statewide over the past decade there remains a diverse mix of both classic "resect" and newer "respect" strategies with comparable short-term outcomes and no major timewise trends. These data may suggest that both approaches are equivocal.
ABSTRACT
Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.
Subject(s)
Drosophila Proteins/genetics , Epilepsy/genetics , Intellectual Disability/genetics , Mutation , X Chromosome , Amino Acid Sequence , Animals , Family Health , Female , Haplotypes , Humans , Male , Mice , Models, Genetic , Molecular Sequence Data , Mutation, Missense , Nucleic Acid Hybridization , Pedigree , Poly A/genetics , Sequence Homology, Amino Acid , Tissue Distribution , Transcription, GeneticABSTRACT
The Omega class glutathione transferase GSTO1-1 can catalyze the reduction of pentavalent methylated arsenic species and is responsible for the biotransfomation of potentially toxic alpha-haloketones. We investigated the cause of GSTO1-1 deficiency in the T-47D breast cancer cell line and found that the cell line is hemizygous for a polymorphic allele that encodes the deletion of Glu155. Northern and Western blots show that T-47D cells contain GSTO1 mRNA but no GSTO1-1 protein suggesting that the deletion of Glu155 causes GSTO1-1 deficiency in vivo. In further support of this contention we found that lymphoblastoid cell lines from subjects who are heterozygous for the deletion of Glu155 have only 60% of normal activity with the GSTO1-1 specific substrate 4-nitrophenacyl glutathione. Pulse-chase studies showed that the deletion of Glu155 causes increased turnover of GSTO1-1 in T47-D cells. These data establish the fact that the polymorphic deletion of Glu155 can cause GSTO1-1 deficiency in vivo. GSTO1-1 expression is elevated in some cell lines that are resistant to the cytotoxic cancer drugs adriamycin, etoposide and cisplatinum but its specific contribution to multi drug resistance has not been evaluated. In this study GSTO1-1 deficient T47-D cells were used to determine if GSTO1-1 contributes directly to arsenic and drug resistance. We established stable expression of normal GSTO1-1 in T-47D cells and found that this did not alter sensitivity to arsenic trioxide, cisplatinum daunorubicin or etoposide.
Subject(s)
Antineoplastic Agents/metabolism , Arsenicals/metabolism , Cytotoxins/metabolism , Drug Resistance, Neoplasm , Glutamic Acid/metabolism , Glutathione Transferase , Oxides/metabolism , Arsenic Trioxide , Cell Line, Tumor , Drug Screening Assays, Antitumor , Genotype , Glutathione Transferase/deficiency , Glutathione Transferase/genetics , Humans , Polymorphism, GeneticABSTRACT
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.
Subject(s)
Epilepsy/genetics , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/genetics , Sodium Channels/genetics , Adolescent , Adult , Age of Onset , Base Sequence/genetics , Child , Child, Preschool , DNA Mutational Analysis/methods , Epilepsies, Myoclonic/genetics , Epilepsies, Partial/genetics , Epilepsy, Generalized/genetics , Humans , Models, Genetic , Mutation/genetics , Mutation, Missense/genetics , NAV1.1 Voltage-Gated Sodium Channel , Parents , PhenotypeABSTRACT
The Human Genetics Society of Australasia is a vibrant professional society with more than 900 members that promotes and regulates the practice of human and medical genetics in Australia and New Zealand. The growth of human genetics was stimulated by the development of diagnostic clinical cytogenetics laboratories in the early to mid 1960s. This coincided with the recognition by medical specialists, mainly pediatricians, that genetic disorders, especially inborn errors of metabolism and birth defects, were of clinical interest and potentially challenging areas for their skills. The organization of professionals in human genetics was slow to evolve. There was an early Western Australian Human Genetics Society, and the cytogenetics community had begun to meet annually from about 1966 but was coordinated by a mailing list rather than as a formal organization. In 1976, as part of the celebrations of the Centenary Year of the Adelaide Children's Hospital, a clinical genetics meeting involving several high profile international speakers and most of the senior medical geneticists in Australia and New Zealand along with the annual meeting of the loose-knit cytogeneticists group agreed that a small working group be charged with setting up a Human Genetics Society. The society was formally incorporated in South Australia in 1977.
Subject(s)
Genetics, Medical/history , Societies/history , Australasia , Cytogenetics/history , History, 20th Century , History, 21st Century , HumansABSTRACT
Numerous cytogenetic and molecular studies of breast cancer have identified frequent loss of heterozygosity (LOH) of the long arm of human chromosome 16. On the basis of these data, the likely locations of breast cancer tumor suppressor genes are bands 16q22.1 and 16q24.3. We have mapped the CBFA2T3 (MTG16) gene, previously cloned as a fusion partner of the AML1 protein from a rare (16;21) leukemia translocation, to the 16q24.3 breast cancer LOH region. The expression of CBFA2T3 was significantly reduced in a number of breast cancer cell lines and in primary breast tumors, including early ductal carcinomas in situ, when compared with nontransformed breast epithelial cell lines and normal breast tissue. Reintroduction of CBFA2T3 into different breast tumor derived cell lines with decreased expression of this gene reduced colony growth on plastic and in soft agar. CBFA2T3 was shown to function as a transcriptional repressor when tethered to the GAL4 DNA-binding domain in a reporter gene assay and, therefore, has the potential to be a transcriptional repressor in normal breast epithelial cells. Taken together, these findings suggest that CBFA2T3 is a likely candidate for the breast cancer tumor suppressor gene that is the target for the frequent 16q24 LOH in breast neoplasms.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 16/genetics , Genes, Tumor Suppressor , Loss of Heterozygosity , Phosphoproteins , Proteins/genetics , Tumor Suppressor Proteins , Cell Division/genetics , Gene Expression Regulation, Neoplastic , Humans , Protein Biosynthesis , Proteins/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Repressor Proteins , Tumor Cells, CulturedABSTRACT
The Omega class glutathione transferases (GSTs) have been identified in many organisms, including human, mouse, rat, pig, Caenorhabditis eglands and Drosophila melanogaster. These GSTs have poor activity with common GST substrates, but exhibit novel glutathione-dependent thioltransferase, dehydroascorbate reductase and monomethylarsonate reductase activities, and modulate Ca release by ryanodine receptors. An investigation of the genomic organization of human GSTO1 identified a second actively transcribed member of the Omega class (GSTO1). Both GSTO1 and GSTO2 are composed of six exons and are separated by 7.5 kb on chromosome 10q24.3. A third sequence that appears to be a reverse-transcribed pseudogene (GSTO3p) has been identified on chromosome 3. GSTO2 has 64% amino acid identity with GSTO1 and conserves the cysteine residue at position 32, which is thought to be important in the active site of GSTO1. Expression of GSTO2 mRNA was seen in a range of tissues, including the liver, kidney, skeletal muscle and prostate. The strongest GSTO2 expression was in the testis, which also expresses a larger transcript than other tissues. Characterization of recombinant GSTO2 has been limited by its poor solubility. Two functional polymorphisms of GSTO1 have been identified. One alters a splice junction and causes the deletion of E155 and another results in an A140D substitution. Characterization of these variants revealed that the A140D substitution affects neither heat stability, nor activity towards 1-chloro-2,4-dinitrobenzene or hydroxyethyl disulphide. In contrast, deletion of residue E155 appears to contribute towards both a loss of heat stability and increased enzymatic activity.
Subject(s)
Glutathione Transferase/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 10 , Cloning, Molecular , DNA, Complementary , Exons , Glutathione Transferase/chemistry , Humans , Molecular Sequence Data , Pseudogenes , RNA, Messenger/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Sequence Deletion , Sequence Homology, Amino Acid , Sequence Homology, Nucleic AcidABSTRACT
BACKGROUND: The CBFA2T3 locus located on the human chromosome region 16q24.3 is frequently deleted in breast tumors. CBFA2T3 gene expression levels are aberrant in breast tumor cell lines and the CBFA2T3B isoform is a potential tumor suppressor gene. In the absence of identified mutations to further support a role for this gene in tumorigenesis, we explored whether the CBFA2T3B promoter region is aberrantly methylated and whether this correlates with expression. RESULTS: Aberrant hypo and hypermethylation of the CBFA2T3B promoter was detected in breast tumor cell lines and primary breast tumor samples relative to methylation index interquartile ranges in normal breast counterpart and normal whole blood samples. A statistically significant inverse correlation between aberrant CBFA2T3B promoter methylation and gene expression was established. CONCLUSION: CBFA2T3B is a potential breast tumor suppressor gene affected by aberrant promoter methylation and gene expression. The methylation levels were quantitated using a second-round real-time methylation-specific PCR assay. The detection of both hypo and hypermethylation is a technicality regarding the methylation methodology.
Subject(s)
Breast Neoplasms/genetics , Phosphoproteins/genetics , Phosphoproteins/metabolism , Promoter Regions, Genetic/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Gene Expression Regulation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Methylation , Phosphoproteins/chemistry , Protein Subunits/genetics , Repressor Proteins/chemistry , Sequence Analysis, DNA/methods , Sulfites/metabolism , Tumor Suppressor Proteins/chemistryABSTRACT
Wolfram syndrome (WFS) is a rare, autosomal recessive neurodegenerative disorder. An increased risk of psychiatric disorders and suicide has been reported for heterozygote carriers. In this study we investigated whether mutations in the WFS gene are associated with suicide in the general population. The gene for WFS (WFS1) has recently been mapped to chromosome 4p16.1, and its genomic structure has been characterized. We screened the entire WFS1 ORF in a panel of 100 completed suicides, 60 blood donors not known to have psychiatric illness, and 100 donors with a negative history of depression or suicidal behavior. We did not find evidence of an increased incidence of WFS carriers in the suicide panel and concluded that WFS1 carrier status is not a significant contributor to suicide in the general population. Screening of this highly polymorphic gene resulted in the detection of 33 variants, 13 of which cause amino acid changes. Seven of these changes have not been previously reported and six were unique to our suicide panel.
Subject(s)
Heterozygote , Suicide , Wolfram Syndrome/genetics , Adult , Alleles , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Gene Frequency , Humans , Membrane Proteins/genetics , Middle Aged , Mutation, Missense , Point Mutation , Polymorphism, Single Nucleotide/genetics , Polymorphism, Single-Stranded Conformational , Wolfram Syndrome/psychologyABSTRACT
Cryptic subtelomeric chromosome anomalies have been recognized as a significant cause of dysmorphology and mental retardation. To determine whether the clinical cytogenetics laboratory should screen routinely for these aberrations, we have tested 250 patients with idiopathic mental retardation/developmental delay, either isolated (53) or associated with dysmorphic features and/or malformations in the absence of a recognizable syndrome (197). All had normal karyotypes at the 550-850 band level. Subtelomeric anomalies were found in 1/53 of the first group (1.9%) and 8/197 of the second group (4.1%). In one patient, two separate anomalies were present: a deletion (not inherited) and a duplication (inherited). It is possible that one of these 10 observed aberrations might represent a rare and previously unreported polymorphism and one a rare cross-hybridization. Our study supports the proposition that cryptic subtelomeric rearrangements are a significant cause of idiopathic mental retardation/developmental delay, but both the diversity of the phenotypes of the positive cases and the wide diversity of their associated chromosome abnormalities emphasize the central problem for the clinical cytogenetics laboratory-that of choosing the most productive patient base for this useful diagnostic test.
Subject(s)
Chromosome Aberrations , In Situ Hybridization, Fluorescence , Intellectual Disability/genetics , Telomere , Adolescent , Child , Child, Preschool , Chromosome Deletion , DNA Probes , Female , Gene Duplication , Humans , Intellectual Disability/etiology , Male , Mass Screening , PedigreeABSTRACT
Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.
Subject(s)
Cadherins/genetics , Chromosomes, Human, X , Codon, Nonsense/genetics , Cognition Disorders/genetics , Epilepsy/genetics , Genomic Imprinting , Mutation, Missense/genetics , Animals , Brain/growth & development , Brain/metabolism , Brain/pathology , Case-Control Studies , Cognition Disorders/pathology , Epilepsy/pathology , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression Regulation, Developmental , Genes, X-Linked/genetics , Humans , In Situ Hybridization , Male , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/pathology , Mice/embryology , Pedigree , Phenotype , Protocadherins , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Skin/cytology , Skin/metabolismABSTRACT
A "new genetics" has emerged driven by knowledge gained at the DNA level. In clinical practice, a practical application of the new genetics is DNA testing, which can be expected to expand with the completion of the Human Genome Project as the functions of new genes are discovered. Genetic DNA testing scenarios include diagnostic DNA testing, prenatal DNA testing, predictive (presymptomatic) DNA testing and screening DNA testing. The challenge for genetic DNA testing and clinical practice will be to define the roles to be played by the general practitioner, the specialist, and other healthcare professionals. From the patients' and families' perspective, the new genetics will best be implemented if a planned approach is adopted in the ordering of DNA tests and the associated counselling and support processes.
Subject(s)
DNA/genetics , Genetics, Medical/legislation & jurisprudence , Genetic Counseling/standards , Genetic Techniques , Genetic Testing/methods , Genetic Testing/standards , Genetics, Medical/standards , HumansABSTRACT
Much is understood about the response of the brain to seizure but little is known in relation to the underlying molecular mechanisms involved. We used microarray technology to investigate the complex genetic response of the brain to generalized seizure. For this investigation a seizure-specific mouse brain cDNA library was generated and spotted onto microarray slides with the aim of increasing the likelihood of identifying novel genes responsive to seizure. Microarray analysis was performed on mouse hippocampus 1 h after generalized seizure pharmacologically induced by pentylenetetrazol (PTZ). Using the custom microarray slides, six genes were identified as being up-regulated in this seizure model and results were validated by real-time PCR. Four of the seizure-responsive genes had previously-reported roles in apoptosis, proliferation or differentiation of neural cells. Two of the genes were novel and in situ hybridization analysis demonstrated heightened mRNA expression in the hippocampus 1 h following generalized convulsive seizure, in a pattern which is typical for other activity-dependant genes expressed in this structure. In addition to being up-regulated postseizure, the genes described in this paper appear to be expressed normally in the adult hippocampus and during development.
Subject(s)
DNA-Binding Proteins/genetics , Nerve Tissue Proteins/genetics , Seizures/genetics , Transcription Factors/genetics , Animals , Base Sequence , Brain/physiopathology , DNA Primers , Hippocampus/physiology , Hippocampus/physiopathology , In Situ Hybridization , Kinetics , Male , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Reference Values , Repressor Proteins , Seizures/physiopathologyABSTRACT
The factor H family of genes has been localised to human chromosome 1q32. This region encodes various proteins involved in complement regulation and is known as the regulators of complement activation (RCA) gene cluster. The factor H genes encode seven known plasma proteins. Using fluorescence in situ hybridisation (FISH), radiation hybrid (RH) mapping and BLAST alignment analysis, we have established that the factor H-related 5 (FHR-5) gene is closely linked to the other factor H gene family members. Analysis of the genomic sequence indicates that the FHR-5 gene is situated between FHR-2 and the non-complement protein factor XIIIb (Fl3B). Like all members of the factor H family. transcription of FHR-5 is in the telomeric direction. Furthermore, the short consensus repeats (SCRs) of FHR-5 are encoded by individual exons and splicing is of type 1. These data allow the generation of a more complete map of the factor H gene family.
Subject(s)
Blood Proteins/genetics , Chromosomes, Human, Pair 1 , Base Sequence , Complement System Proteins , Humans , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Radiation Hybrid Mapping , Sequence AlignmentABSTRACT
Loss of heterozygosity (LOH) of chromosome 16q24.3 is a common genetic alteration observed in invasive ductal and lobular breast carcinomas. We constructed a physical map and generated genomic DNA sequence data spanning 2.4 Mb in this region. Detailed in silico and in vitro analyses of the genomic sequence data enabled the identification of 104 genes. It was hypothesized that tumor-suppressor genes would exhibit marked mRNA expression variability in a panel of breast cancer cell lines as a result of downregulation due to mutation or hypermethylation. We examined the mRNA expression profiles of the genes identified at 16q24.3 in normal breast, a normal breast epithelial cell line, and several breast cancer cell lines exhibiting 16q24.3 LOH. Three of the genes, CYBA, Hs.7970, and CBFA2T3, exhibited variability ten times higher than the baseline. The possible role of these genes as tumor suppressors is discussed.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 16 , Genes, Tumor Suppressor , Loss of Heterozygosity , Female , Gene Expression Profiling , Genetic Predisposition to Disease , Humans , Physical Chromosome Mapping , Sequence Analysis, DNAABSTRACT
X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.
Subject(s)
Genetic Diseases, X-Linked/genetics , Intellectual Disability/genetics , Protein Serine-Threonine Kinases/genetics , Spasms, Infantile/genetics , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 7 , Developmental Disabilities/genetics , Dosage Compensation, Genetic , Female , Genes, Homeobox , Humans , Infant , Molecular Sequence Data , Translocation, GeneticABSTRACT
A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.
Subject(s)
Amino Acid Substitution/genetics , Epilepsy, Generalized/genetics , Genetic Predisposition to Disease , Multifactorial Inheritance , Point Mutation , Receptors, GABA-A/genetics , Epilepsy, Generalized/physiopathology , Female , Heterozygote , Homozygote , Humans , Male , Pedigree , Seizures, Febrile/genetics , Seizures, Febrile/physiopathology , Synaptic Membranes/pathologyABSTRACT
Hemopoietic cells, apparently committed to one lineage, can be reprogrammed to display the phenotype of another lineage. The J2E erythroleukemic cell line has on rare occasions developed the features of monocytic cells. Subtractive hybridization was used in an attempt to identify genes that were up-regulated during this erythroid to myeloid transition. We report here on the isolation of hemopoietic lineage switch 5 (Hls5), a gene expressed by the monocytoid variant cells, but not the parental J2E cells. Hls5 is a novel member of the RBCC (Ring finger, B box, coiled-coil) family of genes, which includes Pml, Herf1, Tif-1alpha, and Rfp. Hls5 was expressed in a wide range of adult tissues; however, at different stages during embryogenesis, Hls5 was detected in the branchial arches, spinal cord, dorsal root ganglia, limb buds, and brain. The protein was present in cytoplasmic granules and punctate nuclear bodies. Isolation of the human cDNA and genomic DNA revealed that the gene was located on chromosome 8p21, a region implicated in numerous leukemias and solid tumors. Enforced expression of Hls5 in HeLa cells inhibited cell growth, clonogenicity, and tumorigenicity. It is conceivable that HLS5 is one of the tumor suppressor genes thought to reside at the 8p21 locus.