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PubMed2003

A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population.

Previous studies have reported genetic linkage evidence for a candidate gene of schizophrenia on chromosome 22q11 but no genes in this region have been really confirmed to be involved in the etiology of schizophrenia so far. Very recently, the proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence for preferential transmission of the PRODH*1945 alleles from parents to affected offsprings was found using either Transmission Disequilibrium Test (P=0.4) or Haplotype-based Haplotype Relative Risk analysis (P=0.35). Our results suggest that the 1945(T/C) polymorphism of the proline dehydrogenase gene is unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.

China↗
PubMed1997

The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-polypeptide in mouse central nervous system.

Mice homozygous for the recessive mutation oscillator (Glra1(spd-ot)) suffer from a complex motor disorder leading to death within three weeks after birth. Symptoms of this disorder mimic poisoning by strychnine, the antagonist of the inhibitory glycine receptor. The syndrome has previously been correlated to a 7 base pair microdeletion within the Glra1 gene (chromosome 11) encoding the alpha1-subunit of the adult glycine receptor isoform. As shown by [3H]strychnine binding and western blot analysis employing subunit-specific antibodies, spinal cord of homozygous oscillator mice was totally devoid of alpha1-polypeptide, characterizing the Glra1(spd-ot) gene as a functional null allele of Glra1. Moreover, tissue levels of the postsynaptic anchoring protein gephyrin were drastically reduced in the Glra1(spd-ot)/Glra1(spd-ot) genotype. In contrast, immunoanalysis revealed a persisting low-level expression of non-alpha1 glycine receptor polypeptides. Spinal glycine receptor content was also significantly reduced in the +/Glra1(spd-ot) genotype. This reduction coincided with increased acoustic startle responses in heterozygous animals consistent with haplotype insufficiency of glycine receptor function. Lethality of the murine null allele Glra1(spd-ot) contrasts with the situation in the human, where homozygosity for a GLRA1 null allele produces the phenotype of the non-lethal disorder hyperekplexia (startle disease; stiff baby syndrome). This suggests a disparate regulation of glycine receptor subunit genes and/or diverse compensatory pathways in mice and humans.

Acoustic Stimulation↗
PubMed2003

Characterization of the human Snrpn minimal promoter and cis elements within it.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are caused by loss of gene function of the imprinted genes including Snrpn within a 2 Mb domain on chromosome 15q11-13. Based on microdeletions in PWS and AS patients, a 4.3 sequence around Snrpn promoter/exon 1, together with a 880 bp sequence upstream to Snrpn, are believed to encompass an imprinting control center for the entire 2 Mb domain. We have previously characterized the mouse Snrpn minimal promoter and a 7 bp element (SBE) within it, which is required for its activity. Here we describe the human Snrpn minimal promoter sequence, which is comprised of a 71 bp upstream sequence and 51 bp of exon 1. The SBE, which has been shown to be critical for mouse promoter activity, is also found in the human sequence and absolutely required for promoter activity. Methylation of this element, like in the mouse, prevents the binding of a protein factor and abolishes promoter activity. In addition, the 5' end of exon 1 must contain cis elements that support promoter activity. In contrast, the 3' end of exon 1 appears to repress promoter activity. This sequence specifically binds a protein factor which presumably exerts a repressory effect on the promoter. Methylation of this sequence prevents the binding of this protein.

Autoantigens↗
PubMed2003

Hypoparathyroidism and facial dysmorphism as main symptoms of 22q.11 deletion syndrome.

A 12-year-old Japanese boy with mental retardation and facial dysmorphism developed frequent convulsions, and hypocalcemia due to hypoparathyroidism was recognized. Chromosomal analysis involving the fluorescence in situ hybridization method revealed a microdeletion of 22q11.2. However, other laboratory examinations revealed no cardiac anomaly, thymic hypoplasia, or cleft palate. It is well known that typical cases of 22q11 deletion syndrome have a cardiac anomaly, thymic hypoplasia and a cleft palate. However, the phenotype of 22q11 deletion syndrome is diverse, and hypoparathyroidism and facial dysmorphism have been reported in nine cases, including this case, associated with 22q11 deletion. This combination of clinical manifestations could be given another term, such as hypoparathyroidism-facial syndrome. Some hypoparathyroidism patients due to 22q11.2 deletion may be misdiagnosed as having idiopathic hypoparathyroidism, and a child diagnosed as having hypoparathyroidism should be examined for chromosomal 22q.11.2. deletion.

Adolescent↗
PubMed2001

A common cis-acting sequence in the DiGeorge critical region regulates bi-directional transcription of UFD1L and CDC45L.

Two to three megabase deletions on chromosome 22q11 are the cytogenetic findings most commonly associated with cardiac and craniofacial defects in humans. The constellation of clinical findings associated with these deletions is termed the 22q11 deletion syndrome. We had earlier described a patient with the 22q11 deletion phenotype who was hemizygous for an atypical 20 kb microdeletion in this region. The deletion included coding regions of two genes organized head-to-head, UFD1L and CDC45L, along with an 884 bp CpG-rich intervening region. Based on this genomic organization, we hypothesized that both genes may be co-expressed and co-regulated by sequences within this region. We demonstrate that expression of both genes is enhanced in a similar pattern in precursors of structures affected by the deletion. The intergenic region is sufficient to direct transcription most strongly in the developing pharyngeal arches and limb buds of transgenic mice and can also direct bi-directional transcriptional activation in a neural crest-derived cell line. Deletion analyses revealed that a 404 bp fragment closest to UFD1L is necessary and sufficient to direct this bi-directional transcriptional activity. These results reveal the presence of a conserved regulatory region in the 22q11 deletion locus that can direct simultaneous transcription of genes involved in ubiquitin mediated protein processing (UFD1L) and cell cycle control (CDC45L).

Adaptor Proteins, Vesicular Transport↗
PubMed2000

Expression patterns of Twist and Fgfr1, -2 and -3 in the developing mouse coronal suture suggest a key role for twist in suture initiation and biogenesis.

Sutural growth depends on maintenance of a balance between proliferation of osteogenic stem cells and their differentiation to form new bone, so that the stem cell population is maintained until growth of the skull is complete. The identification of heterozygous mutations in FGFR1, -2 and -3 and TWIST as well as microdeletions of TWIST in human craniosynostosis syndromes has highlighted these genes as playing important roles in maintaining the suture as a growth centre. In contrast to Drosophila, a molecular relationship between human (or other vertebrate) TWIST and FGFR genes has not yet been established. TWIST mutations exert their effect via haploinsufficiency whereas FGFR mutations have a gain-of-function mechanism of action. To investigate the biological basis of FGFR signalling pathways in the developing calvarium we compared the expression patterns of Twist with those of Fgfr1, -2 and -3 in the fetal mouse coronal suture over the course of embryonic days 14-18, as the suture is initiated and matures. Our results show that: (1) Twist expression precedes that of Fgfr genes at the time of initiation of the coronal suture; (2) in contrast to Fgfr transcripts, which are localised within and around the developing bone domains, Twist is expressed by the midsutural mesenchyme cells. Twist expression domains show some overlap with those of Fgfr2, which is expressed in the most immature (proliferating) osteogenic tissue.

Animals↗
PubMed2001

[Tetralogy of Fallot in monozygotic twins].

UNLABELLED: The causative mechanisms of congenital heart defects remain unclear and little is known about the respective implication of chance, genetics and environment, though recent findings in molecular biology may provide further insight into understanding the pathophysiologic basis of congenital heart diseases. CASE REPORT: We report the exceptional but significant case of monozygotic twins both affected by tetralogy of Fallot, for whom prenatal diagnosis ruled out 22q11 microdeletion. CONCLUSION: We discuss how far this observation is consistent with the latest hypothesis, which emphasizes the leading role of genetic factors. Several genes indeed, either separately or in combination, could be responsible for those defects, even if other influences may still come into play.

Chromosomes, Human, Pair 22↗
PubMed1997

[Smith-Magenis syndrome].

Smith-Magenis syndrome is caused by a 17p11.2 deletion. It associates mental retardation, facial dysmorphism and brachydactyly; aberrant behavior and major sleep problems are present in 70% of the cases. It is probably under-diagnosed because the facial abnormalities are mild and the behavioral problems with hyperactivity and self-injuries are dominant, leading to the diagnosis of psychiatric pathology. However these behavioral problems are sufficiently characterized to allow the diagnosis of the syndrome and look for a 17p11.2 microdeletion. Otorhinolaryngologic, ophthalmologic, cardiac and renal abnormalities can be associated and their evaluation is necessary. Smith-Magenis syndrome is considered as a contiguous gene syndrome. Genes have been mapped and isolated to the critical region, but their participation in the pathogenesis of the syndrome remains unclear.

Abnormalities, Multiple↗
PubMed1997

[Smith-Magenis syndrome].

BACKGROUND: The main features of the Smith-Magenis syndrome include broad flat midface, brachycephaly, broad nasal bridge, brachydactyly, hoarse deep voice, speech and developmental delay, and behavioral anomalies. This syndrome is due to interstitial deletion of chromosome 17p11.2. CASE REPORT: A 7-year-old girl was admitted for mental retardation. Clinical examination showed brachycephaly, broad flat midface, broad nasal bridge, malar hypoplasia, brachydactyly, decreased or absent deep tendon reflexes, and hoarse deep voice. She had a mild deafness, behavioral problems, and sleep disturbances. Chromosome analysis on lymphocytes identified a microdeletion of one chromosome subband 17p11.2. Molecular studies indicated loss of maternal allele. CONCLUSION: The Smith-Magenis syndrome is probably underdiagnosed because of its usually mild clinical features. High-resolution chromosome analysis is needed for diagnosis.

Abnormalities, Multiple↗
PubMed1999

[What's new in pediatric cardiology?].

In recent years, close collaborations have been established between pediatric cardiology, medical and molecular genetics, fetal cardiology and pediatric radiology. As a consequence, several congenital heart defects and syndromes including cardiovascular malformations have been related to microdeletions such as 22q11 in Di George syndrome and 7q in Williams syndrome. Prenatal detection of heart malformations has become a crucial part of the management of life-threatening malformations of the neonate such as the transposition of the great arteries or the coarctation of the aorta. We are at the dawn of a new era of the development of preventive cardiovascular medicine starting from childhood thanks to new techniques of echo-tracking. Finally, three-dimensional reconstruction of heart defects by using ultrasound, X-ray or MRI have dramatically improved the diagnosis and the therapeutic strategies of cardiac diseases.

Cardiology↗
PubMed1988

Genetic causes of mental handicap and opportunities for prevention.

Prior to 1970 nearly one half of severe mental handicap (IQ less than 50) was unexplained and genetic causes were recognized in one third of all patients. In recent years the genetic contribution has risen to 50%, with the decline in importance of environmental causes and the growing recognition of X-linked forms of mental retardation and chromosomal microdeletion syndromes. Recognition of genetic conditions is vital for accurate assessment of recurrence risks and in order, in some instances, to provide specific prenatal diagnosis. With full utilization of existing prenatal screening procedures and a more detailed family history, severe mental handicap due to genetic conditions should be reduced by 30-40%.

Brain↗
PubMed2003

Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population.

Dysferlin, the protein product of the dysferlin gene (DYSF), has been shown to have a role in calcium-induced membrane fusion and repair. Dysferlin is absent or drastically reduced in patients with the following autosomal recessive disorders: limb-girdle muscular dystrophy type 2B (LGMD-2B), Miyoshi myopathy (MM) and distal anterior compartment myopathy. To date, less than 45 mutations have been described in DYSF and a wide inter- and intra-familial variation in clinical phenotype has been associated with the same mutation. This observation underlines the relevance of any new report describing genotype/phenotype correlations in dysferlinopathic patient and families. Here we present the results of clinical, biochemical and genetic analysis performed on one MM and three LGMD Italian families. By screening the entire coding region of DYSF, we identified three novel mutations (two missense substitutions and one frame shift microdeletion). The possible existence of a founder effect for the Arg959Trp mutation in the Italian population is discussed.

Adult↗
PubMed1999

SHOX: pseudoautosomal homeobox containing gene for short stature and dyschondrosteosis.

A growth gene has been postulated, on the basis of genotype-phenotype correlations in patients with sex chromosome aberrations, to exist on the short-arm pseudoautosomal region (PAR1) of the sex chromosomes. Recently, Rao et al. have identified a novel homeobox containing gene, SHOX (short stature homeobox containing gene), from the distal part of PAR1, by means of a positional cloning method. SHOX is most strongly expressed in bone marrow fibroblasts, implying that SHOX plays a positive role in bone growth and development. In addition, SHOX is expressed from an inactive X chromosome, as well as an active X and a normal Y chromosome, suggesting that SHOX escapes X-inactivation and exerts the dosage effect in sex chromosome aberrations. Mutational analysis of SHOX was done in about 400 patients with idiopathic short stature, identifying three types of heterozygous nonsense and missense mutations. Furthermore, fluorescence in situ hybridization analysis of SHOX was performed in six Japanese families with dyschondrosteosis, demonstrating microdeletions involving SHOX in all the patients. The results indicate that SHOX is responsible for short stature and dyschondrosteosis.

Chromosome Mapping↗
PubMed2003

[Genetic origin of spermatogenesis impairments: clinical aspects and relationships with mouse models of infertility].

Human spermatogenesis failures appear frequently as idiopathic and may be due to genetic causes. Mutations of genes involved in the hypothalamic/pituitary control of spermatogenesis have been described and account for several types of hypogonadotropic hypogonadism. Chromosomal abnormalities found in infertile patients are either gonosomal aneuploidies or structural anomalies which interfere with the normal chromosome behaviour at meiosis and lead to germ cell breakdown. Microdeletions of the Y chromosome are often undetectable at karyotype and are responsible for the loss of genes which compose the AZF factor. The increase in the number of mouse models of infertility will allow the description of many human genes involved in the spermatogenesis process provided that a detailed analysis of their genotype-phenotype relationships is performed.

Animals↗
PubMed2005

Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis.

The Y chromosomal azoospermia factor (AZF) is essential for human spermatogenesis. It has been mapped by molecular deletion analyses to three subintervals in Yq11, AZFa, AZFb, and AZFc, containing a number of genes of which at least some control, post-transcriptionally, the RNA metabolism of other spermatogenesis genes, functionally expressed at different phases of the spermatogenic cycle. Intrachromosomal recombination events between homologous large repetitive sequence block in Yq11 are now recognized as the major cause of the AZFa, AZFb and AZFc microdeletions, and an overlap of the AZFb and AZFc regions was revealed by sequence analysis of the complete Yq11 region. The increasing knowledge of the expression patterns of AZF genes in human germ cells suggests that the DBY gene is the major AZFa gene, the RBMY gene the major AZFb gene, although a functional expression of the other AZFa/b genes in the male germ line is also most likely. Genetic redundancy might exist in AZFc because a number of gene copies in the large P1 palindrome structure in distal AZFc were found to be deleted also in fertile men.

Base Sequence↗
PubMedDate not supplied

The Y chromosome.

The Y chromosome has evolved to provide sex determination in mammals. In association with its evolution, genes important for spermatogenesis have been sequestered on this chromosome. Further, X chromosome inactivation has developed as a mechanism to prevent over-expression of genetic factors important for somatic function in females, with maintenance of their activity in males. The multi-repeat organization of the Y chromosome and limited regions of crossover with other chromosomes predisposes it to internal recombination and loss of genes that may be important for spermatogenesis. Y chromosome microdeletion testing of infertile men with non-obstructive azoospermia provides prognostic information useful for management of these patients. In the presence of a complete deletion of the azoospermic factor a (AZFa) or AZFb regions, sperm retrieval is highly unlikely. Recent advances in our understanding of the organization and function of the Y chromosome are likely to enhance further the role of the Y chromosome in normal spermatogenesis and fertility.

Animals↗
PubMedDate not supplied

Male reproductive function and the human Y chromosome: is selection acting on the Y?

The human Y chromosome encodes genes that are essential for male sex determination, spermatogenesis and protection against Turner stigmata. In recent years mutations have been identified in Y-chromosome genes associated with these phenotypes and a series of microdeletions of the long arm of the Y have been defined that are specifically associated with male infertility. In parallel, the discovery of polymorphic markers on the Y, comprising of both slow-mutating binary markers and rapidly-mutating microsatellites, has enabled the high resolution definition of a large number of paternal lineages (haplogroups). These Y-chromosome haplogroups have been extensively used to trace population movements and understand human origins and histories, but recently a growing number of association studies have been performed aimed at assessing the relationship between the Y-chromosome background and Y-linked phenotypes such as infertility and male-specific cancers. These preliminary studies, comparing haplogroup distributions between case and control populations, are promising and suggest an association between different Y-chromosome lineages, sperm counts and prostate cancer. However, we highlight the need to extend these studies to other world populations. Increased sample numbers and a better haplogroup resolution using additional binary markers in association studies are necessary. By these approaches novel associations between Y-chromosome haplotypes and disease may be revealed and the degree to which selection is acting on the human Y chromosome may be determined.

Chromosomes, Human, Y↗