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PubMed1998

Identification of sequence variants and analysis of the role of the catechol-O-methyl-transferase gene in schizophrenia susceptibility.

BACKGROUND: Deletions of 1.5-2 MB of chromosome 22q11 have been previously associated with schizophrenia. The deleted region includes proximally the region harboring genes involved in DiGeorge and velocardiofacial syndromes. Distally, it includes the gene for catechol-O-methyl-transferase (COMT), an enzyme that catalyzes the O-methylation of catecholamine neurotransmitters, including dopamine, and which therefore is considered a candidate gene for schizophrenia. METHODS: We address the issue of a direct involvement of the COMT gene in the development of schizophrenia by employing the first extensive mutational analysis of this gene in a sample of 157 schizophrenia patients and 129 healthy controls, using single-strand conformation polymorphism and chemical cleavage methodologies. RESULTS: No mutations were found, but several sequence variants were identified, including the genetic polymorphism that underlies the high/low activity of the enzyme (a Val158-->Met change, which results in the creation of an NlaIII restriction site in the low-activity allele). The distribution of the NlaIII genotypes among subsets of schizophrenia patients was analyzed. CONCLUSIONS: The results presented here argue against a major role of COMT in schizophrenia in general (although a minor effect could not be excluded) and represent a first step toward a more refined delineation of the phenotype/genotype relationship between 22q11 microdeletions and schizophrenia susceptibility.

Adult↗
PubMed1999

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS: Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.

Adolescent↗
PubMed1999

22q11 deletion syndrome: a genetic subtype of schizophrenia.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

Chromosome Deletion↗
PubMed2000

Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and in vitro studies.

Tremor rat (tm/tm), the parent strain of spontaneously epileptic rat (SER: zi/zi, tm/tm), exhibits absence-like seizures characterized by 5-7 Hz spike-wave-like complexes on cortical and hippocampal electroencephalograms (EEG) after 10 weeks of age, prior to development of convulsive seizures. Recently, this animal model has been demonstrated to display a genomic microdeletion within the critical region of tm, where aspartoacylase hydrolyzing N-acetyl-L aspartate (NAA) is located, besides showing the ability to accumulate NAA in the brain. Therefore, the present study was performed to determine the involvement of NAA in the induction of epileptic seizures. When NAA (4 micromol) was applied intracerebroventricularly (i.c.v.) to normal Wistar rats, 4-10 Hz polyspikes and/or spike-wave-like complexes followed by absence-like seizure before persistent 1-5 Hz waxing high-voltage after-discharges were observed on cortical and hippocampal EEG. At a higher dose (8 micromol), NAA induced convulsive seizures. The absence-like seizures with polyspikes and/or spike-wave-like complexes on the EEG were also observed with i.c.v. NAA in premature tremor rats without seizures. The NAA-induced seizures in normal rats were antagonized by i.c.v. glutamic acid diethyl ester, a non-selective glutamate receptor antagonist. In addition, NAA applied to the bath rapidly induced a long-lasting depolarization concomitantly with repetitive firings in hippocampal CA3 neurons of normal rat brain slice preparations. These findings suggest that NAA is involved in the induction of absence-like seizures and/or convulsion, probably via glutamate receptors.

Animals↗
PubMed2000

Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions.

OBJECTIVE: To determine the prevalence and type of Yq microdeletions in 86 consecutive men that fathered 99 sons by intracytoplasmic sperm injection (ICSI) and to determine the incidence of vertical transmission and de novo deletions in these boys. DESIGN: Prospective clinical observational study. SETTING: Genetics laboratory associated with a university IVF unit. PATIENT(S): Eighty-six consecutive infertile men presenting to an IVF clinic and their 99 ICSI-conceived sons. Fifty of the 86 men (58%) had idiopathic seminiferous tubule failure (STF); the remainder had a variety of other clinical indications for ICSI. INTERVENTION(S): Collection of peripheral and cord blood samples. MAIN OUTCOME MEASURE(S): The Yq genetic status of fathers who underwent ICSI and of their sons by the presence or absence of 22 Y-specific markers covering the four azoospermia factor (AZF) subregions. RESULT(S): Yq deletions of the AZFd/c region were detected in two (6.9%) of 29 azoo- or severely oligospermic men with STF. Identical deletions were found in their respective sons. No de novo deletions were detected in the remaining 97 sons conceived by men without deletions. CONCLUSION(S): The detection of Yq deletions only in men with severe STF is consistent with previous studies, with the AZFd/c region being most commonly affected. This study demonstrates the vertical transmission of these Yq deletions through the use of ICSI and supports the notion that, in most cases, Yq deletions will be inherited by male offspring. The absence of de novo Yq deletions in the male offspring indicates that these events are rare following ICSI in men with both STF and other common male factor indications.

Fathers↗
PubMed2001

Expression of CDY1 may identify complete spermatogenesis.

OBJECTIVE: To investigate the expression of deleted in azoospermia (DAZ), RNA-binding motif (RBM), and chromodomain y1 (CDY1) genes in the testes of men with azoospermia with variable histopathologies. DESIGN: Prospective study. SETTING: Andrology laboratory of a university-affiliated maternity hospital. PATIENT(S): Sixty-six men with azoospermia. INTERVENTION(S): Testicular sperm extraction. MAIN OUTCOME MEASURE(S): The results of gene expression in testicular tissue tested by RT-PCR were correlated with those of histopathologically and microscopically examined minced testicular tissue. Y chromosome microdeletion testing and karyotyping were performed, as was direct sequencing of CDY1-PCR products. RESULT(S): CDY1-minor expression was detected in all biopsies in which mature spermatids/spermatozoa were observed by histological analysis and/or in the minced tissue. CDY1-minor expression was also detected in two biopsies with arrest at the spermatocyte stage during which no mature spermatids/spermatozoa were observed. A previously unreported CDY1-minor alternative splicing transcript was identified. DAZ and RBM gene expressions were detected in all biopsies in which at least a few germinal cells in early stages were found and in one biopsy histologically determined as Sertoli cell only. CONCLUSION(S): Our preliminary results suggest that CDY1-minor expression might increase the prospect for complete spermatogenesis, while RBM and DAZ expression can only be indicative of the presence of germinal cells.

Adult↗
PubMed2003

Genetic analysis of three polymorphic sites of the luteinizing hormone beta-subunit gene in infertile Korean men with nonobstructive azoospermia.

OBJECTIVE: To investigate the genetic background of nonobstructive male factor infertility. DESIGN: Clinical and controlled study. PATIENT(S): Ninety-five nonobstructive male infertile patients (75 with azoospermia, 18 with oligoasthenoteratozoospermia, and two with oligozoospermia) and 200 healthy fertile control men. INTERVENTION(S): Patients were investigated for genetic background including karyotype, Yq chromosome deletion, and three polymorphisms of the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser). MAIN OUTCOME MEASURE(S): To determine three polymorphisms of the LH beta-subunit gene. RESULT(S): An abnormal karyotype was found in 11 of the 75 patients with azoospermia and one of the 18 patients with oligoasthenoteratozoospermia. Eleven (12%) had one or more deleted sites at 13 loci on Yq. The Gly102Ser variant of the LH beta-subunit gene was not detected at all. The frequency of double Trp8Arg and Ile15Thr heterozygotes was similar between the fertile (14.5%, n = 200) and infertile (12.6%, n = 95) groups, with the exception of one homozygous mutation (Arg8 and Thr15) from patient with azoospermia. CONCLUSION(S): Three variants of the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser) may not be associated with male factor infertility. We found one homozygous Arg8 and Thr15 mutation in a patient with azoospermia with normal hormone levels (FSH, LH, PRL, T), a normal karyotype, and no Yq microdeletions.

Adult↗
PubMed1988

An association among blepharophimosis, resistant ovary syndrome, and true premature menopause.

Four cases are described of a very rare association among blepharophimosis, resistant ovary syndrome, and true premature menopause. Plasma levels of follicle-stimulating hormone and luteinizing hormone were significantly elevated and estradiol significantly decreased in all four cases. Ovarian biopsies demonstrated large numbers of unstimulated primordial follicles in three cases and no follicles in one case. Two of the four women were sisters, with the older having true premature menopause and the younger having resistant ovary syndrome. The explanation for the association of blepharophimosis with primary ovarian dysfunction is unknown, but the possibility of a microdeletion of genetic material containing two geographically associated but independent genes could not be confirmed or excluded by high-resolution chromosome banding. All families affected by the autosomal dominant condition of blepharophimosis should be counseled about the high incidence of ovarian dysfunction and female infertility, at least in one form of the syndrome.

Adult↗
PubMed1998

Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection.

OBJECTIVE: To examine the frequency of anomalies of the vas deferens and the frequency of mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in male candidates for intracytoplasmic sperm injection (ICSI) who had severe oligoasthenoteratozoospermia. DESIGN: The clinical data for male candidates for ICSI were studied. The three most frequent cystic fibrosis (CF)-causing CFTR mutations in the Dutch population (deltaF508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens (CBAVD) in the Dutch population (deltaF508, R117H, and IVS8-5T) were analyzed. Delta I507 is also detected by the deltaF508 test. Samples of DNA from patients identified as CFTR mutation carriers were subjected to denaturing gradient gel electrophoresis analysis with use of a two-dimensional electrophoretic technique. SETTING: University-based center for reproductive medicine and clinical genetics. PATIENT(S): Male candidates for ICSI who had oligoasthenoteratozoospermia and no history of operative sterilization and refertilization. Males with a chromosomal aberration or a Y-chromosome microdeletion were excluded. INTERVENTION(S): Semen and blood samples were collected from the patients at their first visit to the clinic. MAIN OUTCOME MEASURE(S): Frequency of anomalies of the vas deferens and frequency of mutations of the CFTR gene in male candidates for ICSI who had oligoasthenoteratozoospermia. RESULT(S): None of the patients had abnormalities of the vas deferens at physical examination. In 4 of the 150 chromosomes (75 patients), a CFTR mutation was found, yielding a CFTR mutation frequency of 2.7% (95% confidence interval, 1.0-6.7%). None of the patients had two CFTR mutations. CONCLUSION(S): The frequency of congenital abnormalities of the vas deferens in patients with oligoasthenoteratozoospermia is low. The frequencies of the CFTR mutations identified in this cohort did not differ significantly from the frequencies found in the normal Dutch population.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed1995

Humoral immunity in DiGeorge syndrome.

OBJECTIVE: To assess humoral immunity after immunization and natural infection in patients with clinical manifestations of the DiGeorge anomalad. DESIGN: Retrospective review of cases. SETTING: Ambulatory immunology clinic of a tertiary care teaching hospital. PATIENTS: The 13 patients had a symptom complex including congenital heart disease, characteristic facies of the DiGeorge anomalad, possible hypocalcemia, and thymic hypoplasia or aplasia. Molecular and cytogenic studies of 12 patients demonstrated that all had 22q11 microdeletions. METHODS: Serial studies included lymphocyte population enumeration by flow cytometry, lymphocyte proliferation assays with the mitogens phytohemagglutinin and pokeweed mitogen and Staphylococcus aureus, and immunoglobulin quantitation. Specific antibody studies included virus neutralization assays for poliovirus antibodies, and enzyme-linked immunosorbent assay for diphtheria, tetanus, measles, rubella, varicella-zoster virus (VZV), and cytomegalovirus (CMV) antibodies. Avidity of rubella, VZV, and CMV antibodies was tested by enzyme-linked immunosorbent assay modified to include a mild protein denaturant in the first wash after incubation with sera. RESULTS: All patients had a CD3+ cell count greater than 0.500 x 10(9)/L and a CD4+ cell count greater than 0.350 x 10(9)/L). One patient had low proliferation responses to S. aureus, and one to phytohemagglutinin and pokeweed mitogen. Immunoglobulin levels, compared with those in age-related control subjects, were normal except that two patients had transient, borderline low IgG levels and two had elevated IgA levels. Specific antibody tests showed (No. of patients with positive results/No. tested) the following: diphtheria (13/13); tetanus (13/13); poliomyelitis caused by polio virus type 1 (5/9), type 2 (9/9), and type 3 (8/9); measles (11/13); rubella (11/13); and infection with VZV (5/5) and CMV (7/13). There were no significant differences in antibody avidity results between patients and control subjects for rubella (mean avidity index, 83.5 +/- 8.79 vs 85 +/- 17.6), VZV (81.6 +/- 3.98 vs 65.1 +/- 12.38), or CMV (69.3 +/- 22.31 vs 73.3 +/- 12.46). CONCLUSIONS: Patients with "partial" DiGeorge anomalad, defined by clinical and immunologic criteria, can be immunized and for the most part can generate good antibody responses.

Adolescent↗
PubMed2002

Schizophrenia-like illness in velo-cardio-facial syndrome: a genetic subsyndrome of schizophrenia?

BACKGROUND: The study of genetic illnesses that have a behavioral phenotype resembling psychosis can provide important insights into the genetic basis of psychotic disorders and their patho-mechanisms. An important example of such a genetic disorder is the velo-cardio-facial syndrome (VCFS) associated with 22q11 microdeletion. CASE REPORT: The case of a 22-year-old male, who had the typical genotype and phenotype of VCFS and developed a psychotic illness characterized by withdrawal, catatonic posturing, inappropriate affect, stereotyped behavior, negativism and poverty of speech, is described. He had a partial response to an atypical neuroleptic, but developed myoclonus that was controlled with an anticonvulsant. CONCLUSION: The association of VCFS with schizophrenia-like psychosis is worthy of further study as it may provide insights into the molecular basis of neurodevelopment and its aberrations in psychotic disorders.

Abnormalities, Multiple↗
PubMed1999

Ionizing radiation and genetic risks. X. The potential "disease phenotypes" of radiation-induced genetic damage in humans: perspectives from human molecular biology and radiation genetics.

Estimates of genetic risks of radiation exposure of humans are traditionally expressed as expected increases in the frequencies of genetic diseases (single-gene, chromosomal and multifactorial) over and above those of naturally-occurring ones in the population. An important assumption in expressing risks in this manner is that gonadal radiation exposures can cause an increase in the frequency of mutations and that this would result in an increase in the frequency of genetic diseases under study. However, despite compelling evidence for radiation-induced mutations in experimental systems, no increases in the frequencies of genetic diseases of concern or other adverse effects (i.e., those which are not formally classified as genetic diseases), have been found in human studies involving parents who have sustained radiation exposures. The known differences between spontaneous mutations that underlie naturally-occurring single-gene diseases and radiation-induced mutations studied in experimental systems now permit us to address and resolve these issues to some extent. The fact that spontaneous mutations (among which are point mutations and DNA deletions generally restricted to the gene) originate through a number of different mechanisms and that the latter are intimately related to the DNA organization of the genes, are now well-documented. Further, spontaneous mutations include those that cause diseases through loss of function as well as gain of function of genes. In contrast, most radiation-induced mutations studied in experimental systems (although identified through the phenotypes of the marker genes) are predominantly multigene deletions which cause loss of function; the recoverability of an induced deletion in a livebirth seems dependent on whether the gene and the genomic region in which it is located can tolerate heterozygosity for the deletion and yet be compatible with viability. In retrospect, the successful mutation test systems (such as the mouse specific locus test) used in radiation studies have involved genes which are non-essential for survival and are also located in genomic regions, likewise non-essential for survival. In contrast, most of the human genes at which induced mutations have been looked for, do not seem to have these attributes. The inference therefore is that the failure to find induced germline mutations in humans is not due to the resistance of human genes to induced mutations but due to the structural and functional constraints associated with their recoverability in livebirths. Since the risk of inducible genetic diseases in humans is estimated using rates of "recovered" mutations in mice, there is a need to introduce appropriate correction factors to bridge the gap between these rates and the rates at which mutations causing diseases are potentially recoverable in humans. Since the whole genome is the "target" for radiation-induced genetic damage, the failure to find increases in the frequencies of specific single-gene diseases of societal concern does not imply that there are no genetic risks of radiation exposures: the problem lies in delineating the phenotypes of recoverable genetic damage that are recognizable in livebirths. Data from studies of naturally-occurring microdeletion syndromes in humans and those from mouse radiation studies are instructive in this regard. They (i) support the view that growth retardation, mental retardation and multisystem developmental abnormalities are likely to be among the quantitatively more important adverse effects of radiation-induced genetic damage than mutations in a few selected genes and (ii) underscore the need to expand the focus in risk estimation from known genetic diseases (as has been the case thus far) to include these induced adverse developmental effects although most of these are not formally classified as "genetic diseases". (ABSTRACT TRUNCATED)

Animals↗
PubMed2006

[Update on the genetics of X-linked mental retardation].

Mutations in X-linked genes are likely to account for the observation that more males than females are affected with mental retardation. Causative mutations have been identified in both syndromic XLMR and in the genetically heterogeneous non-syndromic forms of XLMR, without a clear clinical phenotype other than cognitive deficit. Progress in genome analysis and the establishment of large collaborations between clinical and molecular research teams, especially the European XLMR consortium, have led to the identification of 20 non-syndromic XLMR genes and 25 syndromic XLMR genes. Given the extensive heterogeneity of non syndromic XLMR, different strategies are used for the identification of new genes: linkage analysis, studies of balanced chromosomal rearrangements (X-autosome translocations, microdeletions) and candidate genes strategies by mutation screening in regions of the X chromosome known to be involved in neuronal development and function. Delineating the monogenic causes of XLMR and their molecular and cellular consequences will provide insight into the mechanisms that are required for normal development of cognitive function in humans. Non syndromic XLMR proteins include 5 distinct classes: transmembrane receptors, small GTPases effectors or regulators, enzymes and translational regulators.

Chromosomes, Human, X↗
PubMed2002

Schizophrenia and velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS), the most frequent known interstitial deletion identified in man, is associated with chromosomal microdeletions in the q11 band of chromosome 22. The VCFS phenotype is complex, with multiple congenital abnormalities affecting several tissues and organs, many of which are derived from neural crest cells. Although phenotypic variability occurs, individuals with VCFS have high rates of psychiatric disorder, especially schizophrenia. Additionally, an increased prevalence of chromosome 22q11 deletions has been reported in populations of people with schizophrenia. Furthermore, results of molecular genetic studies suggest that a schizophrenia susceptibility locus maps to chromosome 22q. These data indicate that aside from being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual, VCFS and deletion 22q11 represents the highest known risk factor for the development of schizophrenia. Since the entire sequence of chromosome 22 has now been identified, the study of VCFS offers a timely and uniquely powerful opportunity to identify susceptibility genes for schizophrenia in the general population. Furthermore, the strength of the association between schizophrenia and VCFS has important implications for the clinical management of these disorders.

Adult↗
PubMed2003

Role of TBX1 in human del22q11.2 syndrome.

BACKGROUND: Del22q11.2 syndrome is the most frequent known chromosomal microdeletion syndrome, with an incidence of 1 in 4000-5000 livebirths. It is characterised by a 3-Mb deletion on chromosome 22q11.2, cardiac abnormalities, T-cell deficits, cleft palate facial anomalies, and hypocalcaemia. At least 30 genes have been mapped to the deleted region. However, the association of these genes with the cause of this syndrome is not clearly understood. METHODS: To test for the chromosomal deletion at 22q11.2, we did fluorescence in-situ hybridisation analysis with ten probes on 22q11.2 in 235 unrelated patients with clinically diagnosed del22q11.2 syndrome. To investigate mutations in the coding sequence of TBX1, we also did genetic analysis in 13 patients from ten families who have the 22q11.2 syndrome phenotype but no detectable deletion of 22q11.2. FINDINGS: 96% (225 of 235) of patients had a defined 1.5-3-Mb deletion at 22q11.2. We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome. We did not record these three mutations in 555 healthy controls (1110 chromosomes; p<0.0001). INTERPRETATION: Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q11.2 syndrome. Therefore, we conclude that TBX1 is a major genetic determinant of the del22q11.2 syndrome.

Abnormalities, Multiple↗
PubMed2001

Congenital fibrosis of the extraocular muscles associated with cortical dysplasia and maldevelopment of the basal ganglia.

BACKGROUND: Congenital fibrosis of the extraocular muscles (CFEOM) is a rare condition that has been traditionally regarded as a primary eye muscle disease. Recent studies, however, suggest that CFEOM may be the result of a primary neuropathy with secondary myopathic changes. PURPOSE: To describe a previously unrecognized association between congenital fibrosis of the extraocular muscles and structural abnormalities of the brain. DESIGN: Small case series. METHODS: Detailed clinical examinations and neuroradiologic studies were performed on the three affected family members. In addition, genetic analysis of the family was performed. RESULTS: The three affected family members, mother and two children, have the ocular features of 'classic' congenital fibrosis of the extraocular muscles. All showed dilation of the left lateral ventricle secondary to hypoplasia of the body and tail of the ipsilateral caudate nucleus. There was fusion of an enlarged caudate nucleus head with the underlying putamen. Both children showed widespread bilateral cortical dysplasia. Genetic analysis of the family was inconclusive but consistent with linkage to the CFEOM1 locus on chromosome 12. Chromosomal analysis of the affected individuals did not show evidence of a deletion of chromosome 12 and haplotype analysis was not suggestive of a microdeletion. CONCLUSIONS: Cerebral cortical and basal ganglia maldevelopment can be found in individuals with CFEOM. This suggests that neuroimaging should be considered in the initial diagnostic evaluation of these patients, particularly if there is developmental delay.

Abnormalities, Multiple↗
PubMed2000

GNB1L, a gene deleted in the critical region for DiGeorge syndrome on 22q11, encodes a G-protein beta-subunit-like polypeptide.

CATCH 22 syndromes, which include DiGeorge syndrome and Velocardiofacial syndrome, are the most common cause of congenital heart disease which involve microdeletion of 22q11. Using a strategy including EST searching, PCR amplification and 5'-RACE, we have cloned a 1487 bp cDNA fragment from human heart cDNA library. The cloned GNB1L cDNA encodes a G-protein beta-subunit-like polypeptide, and the GNB1L gene is located in the critical region for DiGeorge syndrome. A comparison of GNB1L cDNA sequence with corresponding genomic DNA sequence revealed that this gene consists of seven exons and spans an approximately 60 kb genomic region. Northern blot analysis revealed GNB1L is highly expressed in the heart.

Amino Acid Sequence↗
PubMed1998

Genetic abnormalities and male infertility. A comprehensive review.

The development of assisted reproductive technologies, such as intracytoplasmic sperm injection (ICSI) substantially improved the outlook for patients with severe male fertility problems. However this implies that for the first time genetic defects associated with male in- or subfertility might be transmitted to offspring and result in genetic disease [de Kretser DM, The potential of intracytoplasmic sperm injection (ICSI) to transmit genetic defects causing male infertility. Reprod. Fertil. Dev. 1995;7:137-142]. The knowledge of male specific fertility genes on the Y chromosome increased enormously in the last decade. The SRY gene plays a critical role in gonadal differentiation. DAZ, SPGY and related genes on the Y chromosome are very important for spermatogenesis. Interstitial Y-chromosomal microdeletions encompassing the AZFa, b or c region have become an additional class of genetic abnormalities causing male infertility. A review is given of the different genetic aspects of male infertility.

DNA-Binding Proteins↗