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PubMed2005

[Using multiplex PCR to analyze the breakpoint of a severe Y-chromosome deletion].

OBJECTIVE: To elucidate the relationship between azoospermia factor(AZF) microdeletion of Y chromosome and azoospermia, the exact breakpoint of a severe Y-chromosome deletion was determined according to the physical map of AZF. METHODS: Multiplex polymerase chain reaction was used to amplify fifteen sequence tagged sites (STS), namely sY82, sY84, sY86 in AZFa, sY124, sY127, sY128, sY133, sY134, sY143 in AZFb, sY239, sY242 sY254, sY255 in AZFc, and sY145, sY152 in AZFd; sex-determining region Y(SRY) was taken as an internal control. And then sY82,sY86,sY85,sY84 were further analyzed using the sample of the patient who had Y-chromosome deletion by G band analysis to map the breakpoint at molecular level. RESULTS: All 15 STS and sY85 were amplified in positive control while only sY82, sY86 were amplified in the clinical sample, thus the breakpoint was found to be between sY86 and sY85. CONCLUSION: This study on the patient provided the direct biomolecular evidence of the exact breakpoint of the severe Y-chromosome deletion and established the deletion map of acrocentric chromosome. It also proved that the patient's azoospermia was due to the deletion of AZF.

Azoospermia↗
PubMed2005

[The relationship between abnormity of synaptonemal complex and male fertility impairment in human].

It was said that 11% of all men showed their infertility. The genetic origins of male infertility may be classified into three main groups: chromosome abnormalities, microdeletions and gene mutations. Growing literature has shown that spermatogenesis failure or reproductive failure (pregnancy wastages) occurred in male carriers of chromosomal distortion/aberration. But the mechanisms remain largely unsolved. Synaptonemal complex (SC) of human spermatocytes from such carriers offers new information. This review aims to summarize recent development of SC analysis for male infertile diagnosis and sum up our results obtained recently. The relationship between male infertility/sterility and SC abnormity was discussed and reviewed as following five aspects. (1) The association of XY-bivalent and the rearranged autosomes interfere with or affect, by their contact, X chromosome normal functions. (2) Male infertility is related to the incomplete pairing in break regions of rearranged autosomes. (3) SC fragmentation, lateral elements (LEs) swelling and pairing disorder result in spermatogenic failure. (4) This heterosynapsis at early stage of meiosis in rearranged autosomes, results in unbalanced germs and pregnancy wastages. (5) Gene mutations of SC proteins result in male infertility.

Animals↗
PubMed2006

[Chromosomal causes that produce mental retardation: chromosome disorders that can be diagnosed in the patient].

INTRODUCTION: In all the aetiological studies carried out on idiopathic mental retardation (MR), chromosomal abnormalities are the factor that makes the most significant contribution. The alterations are more frequent when severe MR is accompanied by a dysmorphic phenotype, but can also be found in subjects with mild MR and with few signs of dysmorphism. DEVELOPMENT: This work reports on new genes and critical regions in syndromes with microdeletion, such as Wolf-Hirschhorn, Smith-Magenis and Sotos--which must be taken into account in the genetic diagnosis--and new microduplications like 15q11-q13, which is associated to a behavioural phenotype of autism. The application of new molecular techniques, such as fluorescent in situ hybridisation (FISH) with multiple telomere probes, MLPA (multiplex ligation-dependent probe amplification) and array-CGH (microarray based on compared genomic hybridisation), have shown the important role played by subtelomeric and interstitial rearrangements in the aetiology of MR. Subtelomeric alterations contribute to between 5 and 7% of cases of idiopathic MR, the higher proportion corresponding to deletions, one of the most common of which is deletion 1p36. Studies that evaluate the global genome in idiopathic MR detect from 7% to 20% of cases with anomalies, the interstitial type being more frequent than the subtelomeric kind. CONCLUSIONS: The application of new technologies to idiopathic MR opens up a promising new field for the diagnosis of new syndromes with submicroscopic alterations, so that a prognosis can be determined, treatment can be improved and the risk of relapse can be defined.

Chromosome Disorders↗
PubMedDate not supplied

Role of testicular fine-needle aspiration cytology in infertile men with clinically obstructive azoospermia.

BACKGROUND: Azoospermia due to obstruction of the vaso-epididymal junction is one of the few surgically correctable causes of male infertility. In patients where all clinical and laboratory parameters suggest a vaso-epididymal junction block amenable to surgery, failure to find normal spermatogenesis on fine-needle aspiration cytology (FNAC) of the testis may necessitate a change in treatment modality to the more expensive intracytoplasmic sperm injection. We evaluated the validity of FNAC findings in predicting failure of surgical exploration when clinical parameters suggest otherwise. METHODS: Infertile, azoospermic men in whom the semen volume and fructose content, testis size, follicle-stimulating hormone level were normal and the vas deferens was palpable with no evident cause for obstruction, underwent FNAC of the testis to confirm the presence of normal spermatogenesis before surgical exploration. Men with hypospermatogenesis or maturation arrest on FNAC and a normal karyotype with absence of Y chromosome microdeletion were offered assisted reproduction or surgical exploration to identify a reconstructable obstruction. Men who chose surgery were included in the study and the findings on exploration were compared with the FNAC reports. RESULTS: Of the 10 men who satisfied the inclusion criteria, 6 had hypospermatogenesis and in 4 FNAC showed maturation arrest. On surgical exploration, none had sperm in the epididymis. A biopsy of the testis taken at the time of exploration confirmed the FNAC findings. CONCLUSION: Clinical parameters are insufficient for diagnosing obstructive azoospermia. FNAC can accurately evaluate the testicular pathology and predict whether or not surgical exploration should be undertaken.

Adolescent↗
PubMed2006

[Left heart defects and genetics].

The obstructive cardiac defects of the left heart are an heterogeneous group of malformations. These past years their molecular bases have been partially understood. The associated chromosomal anomalies are mainly represented by the Turner syndrome, the microdeletion of the chromosome 11q and the 7q23 deletion in Williams syndrome. In isolated obstructive left heart diseases, new insights into their genetic bases have been made because the dominant inheritance has been demonstrated and the notion of a phenotypic continuum between bicuspid aortic valve and the complete form of hypoplastic left heart has been proposed. Finally, mutations in genes involved in heart development, namely NKX2.5 and NOTCH1, have been identified in these defects and support the former hypotheses. The low penetrance and the variable expression of these known mutations did not completely solved prenatal genetic counselling.

Chromosome Aberrations↗
PubMed2006

AZF deletions in infertile men from the Republic of Macedonia.

Y chromosome deletions in the three azoospermia factor (AZF) regions constitute the most common genetic cause of spermatogenic failure. The aim of this study was to estimate the length and boundaries of the AZF deletions and to correlate the AZF deletions with the sperm concentrations, testicular histology, Y haplogroups and the ethnic origin of the men with deletions. PCR analysis of STS loci in the three AZF regions was used to characterize the deletions. Y haplogroup was predicted from a set of 17 Y short tandem repeats (STR) marker values. A total of nine men out of 218 infertile/subfertile men showed the presence of Y microdeletions. In eight patients the results were consistent with the presence of AZFc deletions, while in one patient a larger deletion involving both AZFb and AZFc regions was detected. In two patients, the deletion, initially diagnosed as AZFc, involved part of the distal part of the AZFb region and in one of them the deletion also extended into the region distal to the AZFc. The 3.5 Mb AZFc deletion, due to homologous recombination between b2 and b4 amplicons, was detected in six men (66.7% of all Y deletions), thus being the most common type of AZF deletion among infertile men from the Republic of Macedonia. Patients with the 3.5 Mb AZFc deletion had azoospermia or severe oligozoospermia and variable histological results [Sertoly cell only syndrome (SCOS), maturity arrest (MA) and hypospermatogenesis (HSG)]. They were of different ethnic origin (Macedonian, Albanian and Romany) and belonged to different Y haplogroups (I1b, J2, E3b and G).

Azoospermia↗
PubMed2006

Androgen receptor CAG polymorphism (Xq11-12) status and human spermatogenesis: a prospective analysis of infertile males and their offspring conceived by intracytoplasmic sperm injection.

We determined the association of androgen receptor (AR) (CAG)n lengths among fertile and infertile males and offspring conceived by intracytoplasmic sperm injection (ICSI). Assessment of (CAG)n repeats in the AR was performed in a Caucasian population by gene sequencing in fertile men (n=13), infertile men (n=64), boys conceived after ICSI (n=21), and boys conceived naturally (n=11). In the AZF region of the Y chromosome, a total of 22 STSs were analyzed by multiplex PCR; selected spermatozoa were also analyzed by fluorescent in situ hybridization (FISH) for chromosomes 18, 21, X, and Y. The average age was 43.7+/-7 yr for infertile, 44.8+/-7 yr for fertile men, and 5.0+/-0.5 yr for the children. The mean (CAG)n was 22.2+/-3 for the infertile men and 19.3+/-5 for fertile controls. There was a significant difference in CAG repeat length in the severely oligo-/azoo-spermic men vs. controls (p=0.02). An inverse correlation was evident between CAG length and semen parameters. For ICSI male children, the AR (CAG)n lengths were 21.4+/-3.2 vs. 20.8+/-3.4 for boys conceived naturally. While all peripheral karyotypes of fertile and infertile men were normal, de novo gonosomal abnormalities were observed in the ICSI offspring. The incidence of Y microdeletions was 1.6% in infertile men; all the ICSI sons had an intact Y chromosome. In conclusion, severely oligo- and azoospermic men had longer CAG repeat length than fertile controls, suggesting that certain AR gene mutations may have a negative effect on spermatogenesis. An increased incidence of de novo gonosomal abnormalities was found in the ICSI offspring when compared to children conceived naturally. Our assessment of the polymorphic region of the AR gene, in the absence of other specific genomic abnormalities, suggests that the fertility of children conceived by ICSI may be conserved.

Adult↗
PubMed2004

[Genetic causes of male infertility].

7% of all human males suffer from infertility. In at least 10% of these males infertility is due to genetic causes. Because modern reproduction techniques like ICSI (intracytoplasmic sperm injection) can help the couples to overcome infertility, it is mandatory to analyze underlying genetic causes of male infertility. If infertility in a male is due to a genetic defect, the risk of the respective couple for abortuses or malformed children is increased. The main and relevant causes for male infertility known to day are: numerical and structural chromosomal aberrations, meiotic defects, microdeletions in the region q11.21-23 of the Y-chromosome, mutations in the gene for cystic fibrosis and genetically determined syndromes in which infertility is a symptom. The present knowledge concerning these genetic causes of male infertility is pointed out.

Chromosome Aberrations↗
PubMed2006

Rubinstein-Taybi syndrome and familial Mediterranean fever in a single patient: two distinct genetic diseases located on chromosome 16p13.3.

Rubinstein-Taybi syndrome (RTS) is characterized by typical facies, short stature, mental retardation, broad thumbs and broad great toes. The syndrome is at least in part caused by microdeletions at chromosome 16p13.3 or by mutations in the gene for the CREB binding protein (CBP), which is located at 16p13.3. Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF-gene [Mediterranean fever (MEFV)] and characterized by recurrent attacks of fever and peritonitis, arthritis and pleuritis. The FMF gene (MEFV) has recently been cloned by two consortia and 30 point mutations, causing the disease have been identified. MEFV maps to chromosome 16p and encodes a 781-amino-acid protein called pyrin or marenostrin, which is expressed mainly in neutrophils and myeloid bone marrow precursors. Herein, we report a case with RTS and FMF.

Adolescent↗
PubMed1991

Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization.

Fluorescence in situ hybridization (FISH) using two cosmid probes (41A and P13) from the Miller-Dieker syndrome (MDS) critical region in 17p13.3 was performed in a blinded comparison of three MDS patients with submicroscopic deletions and in four normal relatives used as controls. The controls showed both chromosome 17 homologues labeled in 85%-95% of cells, while each patient showed only one homologue labeled in 75%-80% of cells. Two MDS patients with cryptic translocations were also studied. In one case, a patient and her mother had the same der(17) (p+), but the reciprocal product of the translocation could not be identified in the mother by G-banding (i.e., it was a "half-cryptic" translocation). FISH revealed a 3q;17p translocation. The other case involved a patient with apparently normal karyotype. Because a large molecular deletion was found, a translocation involving two G-negative telomeres (i.e., a "full-cryptic" translocation) was postulated. FISH studies on her father and normal brother showed an 8q;17p translocation. These studies demonstrate that in situ hybridization is an efficient method for deletion detection in Miller-Dieker syndrome. More important, parental studies by FISH on patients demonstrating molecular deletions and a normal karyotype may identify cryptic translocation events, which cannot be detected by other molecular genetic strategies. Similar in situ strategies for deletion detection can be developed for other microdeletion syndromes, such as Prader-Willi/Angelman syndrome or DiGeorge syndrome.

Abnormalities, Multiple↗
PubMed1991

Neuroblastoma in a dwarfed newborn. Possible clue to the chromosomal localization of the gene for achondroplasia?

The authors report a premature achondroplastic child with connatal neuroblastoma. Though this association could be coincidental, we suggest that a microdeletion inducing a contiguous gene syndrome involving the locus of neuroblastoma suppressor gene could be an alternative hypothesis. The gives a working hypothesis for the localization of the gene for achondroplasia.

Achondroplasia↗
PubMedDate not supplied

[Transposition of the composite synthetic transposon TnV (Tn5-Rep(pSC101)) is accompanied by the formation of the mini-plasmid pTnV, containing defective Is50-elements].

Using thermoelimination (at 42 degrees C) of the thermoinducible coliphage P1tsCmr omega::TnV (TnV is a Tn5 derivative which contains the replication origin (Rep) of plasmid pSC101), more than 110 KmrCms Escherichia coli K12 clones were selected. It was supposed that the KmrCms phenotype could result only from insertion of TnV (Kmr) into E. coli chromosome and the loss of phage (Cms). It was found that the majority of KmrCms clones (35-90%) contained miniplasmids. Their molecular sizes did not exceed the TnV size (6.1 kb). The formation of miniplasmids called pTnV was observed both in RecA+ cells (C600) and in RecA- (HB101), more often in the latters. Interestingly, that miniplasmids of only several molecular sizes were detected: from 6.1 kb (pTnV60) to 4.35 kb (pTnV43). A restriction analysis showed that DNA of the majority of pTnV plasmids had varying deletions (0.3-1.3 kb) of mainly IS50L element which together with IS50R flank TnV. Very low transposition frequencies (approx. 10(-8) Kmr transconjugants per transferred R388) of all pTnV types (including pTnV60 plasmids containing probably microdeletions of the joining "outside" IS50's ends) suggest that pTnV plasmids are not intermediates in TnV transposition. Possibly the circularized TnV derivatives (pTnV's) are side products of the transposition resulting from the abortive attempts of an excised and autonomous transposon molecule to insert into itself. In the present paper the possible mechanisms of the origin of limited pTnV type numbers are also discussed.

Coliphages↗
PubMed1990

Identification of the functional profilin gene, its localization to chromosome subband 17p13.3, and demonstration of its deletion in some patients with Miller-Dieker syndrome.

Profilin is a conserved actin-monomer-binding protein which is found in all eukaryotes, including yeast. Although amino acid sequence analysis and RNase protection analysis suggest a single profilin isoform in mammalian cells, Southern blot analysis of human and somatic cell hybrid DNA indicates several loci in the human genome which hybridize with the profilin cDNA. We therefore isolated human genomic clones to analyze these genetic loci in detail. Only one of the cloned loci has typical features of a functional gene, including upstream transcriptional elements and typical exon-intron structure. Four other isolated loci are all diverged, intronless pseudogenes and are likely to be nonfunctional. The functional gene was localized to human chromosome band 17p13 by analysis of somatic cell hybrids and by in situ chromosomal localization. The Miller-Dieker syndrome (MDS), a rare congenital disorder manifested by characteristic facial abnormalities and lissencephaly (smooth brain), is associated with microdeletions of the distal 17p region. RFLP analysis of a patient with MDS, and analysis of somatic cell hybrids containing partially deleted chromosomes 17 from patients with MDS, using the profilin gene probe, indicate that profilin is localized to chromosome subband 17p13.3. These results also indicate that profilin is the first identified cloned gene which is part of the genetic material deleted in some patients with MDS but that other patients have smaller deletions not affecting the profilin locus. Thus, single allelic deletion of the profilin locus may contribute to the clinical phenotype of the MDS in some patients but does not play a major role in the essential phenotype.

Amino Acid Sequence↗
PubMed1990

[Prader-Willi-Labhart syndrome: relations with the hypothalamus and chromosome 15].

The Prader-Willi syndrome is a human disease whose physiological causes have not yet been elucidated. However, clinical and biological parameters suggest that it is an hypothalamic disorder. This syndrome is the most common form of human congenital obesity. In many cases, the genetic alteration has been identified as a microdeletion in the chromosomal region 15q11-q13. Consequently, one can presume that obesity in patients with Prader-Willi syndrome is the result of some hypothalamic deficiency involving the products of one or several genes found in this region of chromosome 15. Several DNA markers belonging to this genomic region have been isolated. If these are fragments of expressed genes, it may be possible to examine the possible association of their products with the hypothalamus and the disease. Such studies may provide new insights into the role of the hypothalamus in the pathophysiology of obesity.

Chromosome Deletion↗
PubMed1990

Autosomal mendelian disorders and microcytogenetics.

The development of cytogenetic high resolution banding techniques has allowed the observation of specific chromosome rearrangements--i.e. microdeletions, translocations--in patients with morbid conditions suspected to have a genetic component but for which a precise etiology had not, or rarely, been recognized. The most striking examples are retinoblastoma, the WAGR complex, Beckwith-Wiedemann syndrome, Langer-Giedion syndrome, Prader-Willi syndrome, Miller-Dieker syndrome and others, which thus could be mapped to the genome. Molecular technology further allowed in a number of cases cloning of the genes proper or of linked DNA polymorphisms permitting genetic counseling.

Chromosome Aberrations↗
PubMedDate not supplied

[Associated forms of hereditary chorioretinal degeneration].

A retrospective study of 324 cases of chorioretinal heredodegeneration of all kinds shows an associated pathology in 44% of cases. These associated anomalies point out the need of a complete physical examination, a familial inquest keeping in mind genetic counseling. They are a good model for a high resolution cytogenetic study to find microdeletions which can allow to precise the genome's map.

Choroid Diseases↗
PubMed1987

Human ferritin genes: chromosomal assignments and polymorphisms.

The ferritins are a family of proteins that function intracellularly to sequester iron that otherwise would be toxic to the cell. The molecules are comprised of 24 heavy and light subunits, the heavy:light ratio varying widely in a tissue-specific manner. We cloned DNA sequences for both the heavy (HL217-1) and light (HL227) subunits from a cDNA library derived from messages that are strongly regulated during in vitro-induced differentiation of a promyelocytic leukemia cell line, HL-60, into either neutrophils or macrophages. The heavy-subunit family (FTH) includes 15-20 genes and/or pseudogenes; the light-subunit family (FTL) includes at least three genes. We have confirmed and extended the chromosomal localization of the heavy-subunit "genes" to chromosomes 1-6, 8, 9, 11, 13, 14, 17, and X. We have also identified and characterized two genetic polymorphisms: FTH/BamHI and FTH/TaqI. FTH/BamHI localizes to chromosome 3, is biallelic, and has a heterozygosity frequency of .39, a minor allele frequency of .33, and a polymorphic information content (PIC) of .34. FTH/TaqI is measured by the presence or absence of a single 6-kb fragment that is absent (i.e., "homozygosity" being presumed) in approximately 63% of Caucasians (PIC = .27). We discuss the possibility that gene-family probes that hybridize to many discrete members of dispersed gene families could be used in conjunction with pulsed- or inverted-field gels to screen a large number of specific genomic regions for microdeletions.

Alleles↗
PubMed1988

Myopathy in complex glycerol kinase deficiency patients is due to 3' deletions of the dystrophin gene.

DNA samples from nine previously reported patients with X-linked recessive glycerol kinase deficiency, associated in seven of them with adrenal hypoplasia and in five with developmental delay and myopathy, have been studied for deletions of the Duchenne/Becker muscular dystrophy gene by probing with the entire cDNA for the dystrophin protein. All five patients with myopathy, including two in whom no deletions had been detected before, were found to have variable-sized deletions extending through the 3' end of this gene. The 5' deletion breakpoints are intragenic in four cases and have been mapped precisely on the exon-containing HindIII fragment map. A correlation was found between severity and progression of the muscular dystrophy phenotype and the sizes of the gene deletions. In cases in which there was glycerol kinase deficiency/adrenal hypoplasia microdeletion syndrome without myopathy, no deletions were found with the dystrophin cDNA.

Chromosome Deletion↗