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PubMed1994

New aspects of the aetiology of male fertility disorders.

Classification of male fertility disorders should take into account the cause and severity of a disturbance as well as its effect on the fertilizing capacity of spermatozoa. A reasonable approach is the analysis of sperm morphology according to the Düsseldorf classification, which is based on defects of spermatid differentiation. The kind and frequency of malformed spermatozoa allow conclusions about basic testicular and epididymal disorders, which will facilitate the detection of epididymal sperm motility disturbances and, therefore, initiation of causal treatment. The effect of inflammatory processes on fertility depends on the site of inflammation. In addition, the necessity for varicocele treatment can be determined more exactly under consideration of sperm morphology and hormonal tests. So far, irregular chromatin condensation as a cause of disturbed male fertility has not been attributed to genetic reasons, whereas microdeletions of the Y chromosome are increasingly being discussed. Both the role of oxygen radicals and the significance of environmental factors need to be investigated in the future.

Adult↗
PubMed2003

Genetic factors in assisted reproduction.

It is still unclear whether the procedures of assisted reproduction increase the risk of congenital malformations. Thus, it remains to be clarified whether an increased risk, if any, of congenital malformations in these children is caused by the procedure of assisted reproduction itself or by the underlying maternal and paternal background. From the genetic point of view, infertility patients seeking assisted reproduction have to be classified as a high-risk group. The prevalence of numerical chromosomal abnormalities is around 10% in these patients, compared with 0.85% in the general population. The prevalence of structural chromosomal abnormalities is around 0.1% in the general population and is increased up to 1% in patients seeking assisted reproduction. In addition, patients with microdeletions of the Y-chromosome or mutations in the cystic fibrosis transmembrane-conductance regulator gene are likely to be encountered at the fertility clinic. Therefore, genetic screening and counselling should be routinely offered to infertility patients. They also need to understand that parental factors can be transferred to offspring that would most likely not have been conceived by natural means.

Adult↗
PubMed2000

The role of human and mouse Y chromosome genes in male infertility.

It was suggested by Ronald Fisher in 1931 that genes involved in benefit to the male (including spermatogenesis genes) would accumulate on the Y chromosome. The analysis of mouse Y chromosome deletions and the discovery of microdeletions of the human Y chromosome associated with diverse defective spermatogenic phenotypes has revealed the presence of intervals containing one or more genes controlling male germ cell differentiation. These intervals have been mapped, cloned and examined in detail for functional genes. This review discusses the genes mapping to critical spermatogenesis intervals and the evidence indicating which are the most likely candidates underlying Y-linked male infertility.

Animals↗
PubMed2000

RBMY genes and AZFb deletions.

Microdeletions of the AZFb region of the human Y chromosome usually result in severe consequences for spermatogenesis. AZFb contains at least four kinds of genes/gene families. These include a number of RBMY genes, which are clustered in the AZFb deletion interval. They are amongst the oldest genes on the mammalian Y chromosome, and are related to the gene encoding hnRNPG (RBMX) on the X chromosome. A retroposon-derived version of these genes is found on chromosome 11 that might replace the function of these genes during meiosis, during which time the X and Y chromosomes are transcriptionally inactivated. Each of these genes encodes proteins with an RNA binding motif, and interacts with more ubiquitously expressed proteins involved in pre-mRNA splice site selection. These findings imply that important pre-mRNA processing pathways might be disrupted in the germ cells of AZFb men.

Animals↗
PubMed2000

Characterization of novel genes in AZF regions.

The long arm of the Y chromosome contains genes mapped in loci involved in male infertility, short stature and gonadoblastoma. However, many of these genes have not been fully characterized, and are not currently investigated in patients affected by such diseases. We report a study aimed to the genomic characterization of 5 genes mapped within the Y chromosome: BPY2, PRY, TTY1, TTY2, and VCY. Exon-intron boundaries were detected for each gene, and PCR analysis was carried out to investigate the involvement of these genes in different re-arrangements of the Y chromosome. It was found that BPY2 and PRY are lost in some infertile patients with Yq microdeletions, suggesting that they could play a role in male gametogenesis. On the other hand, these patients retain some copies of TTYI and TTY2 genes, due to the presence of copies in Yp, and of VCY, which has homologous copies on the X chromosome. On the basis of their localization, these genes could be candidate for the gonadoblastoma locus (TTY1, TTY2) and for the control growth locus (VCY).

Base Sequence↗
PubMed2002

Abnormalities of GH secretion in a young girl with Floating-Harbor syndrome.

We present a 9.1-year-old girl of Calabrian (Italy) ancestry, with clinical features (cranio-facial dysmorphism, short stature with delayed bone age and speech delay) suggesting the diagnosis of Floating-Harbor syndrome (FHS). Physical examination showed: height 113.9 cm (-2.9 SD), with a parent's target of 156.2 cm (+1.0 SD), weight 20.7 kg, BMI 16.0 (-0.04 SD), and many phenotypic abnormalities: long eyelashes, large bulbous nose with broad nasal bridge, short philtrum, moderately broad mouth, tooth folding and malocclusion, posteriorly rotated ears, low posterior hair line, short neck, clinodactyly of the 5th finger and hyperextensible finger joints. Diffused hyperpigmentation and hypertrichosis with sporadic pubic terminal hairs, but neither clitoromegaly nor other signs of hyperandrogenism and/or precocious puberty, were observed (T1, P1). Carpal bone evaluation showed a delayed bone age (TW2: 5-5/10, - 3.6 yr) and the statural age/bone age ratio was 1.1. Other dysmorphic syndromes were excluded on the basis of clinical evidence, also evaluated by a computer-assisted search (P.O.S.S.U.M. version 3.5, 1992). Analysis of chromosome 22 by the FISH method, using specific probes Cos29 and Tuple1, excluded microdeletions in the region 22q11.2, typical of Velo-cardio-facial syndrome. In this case, we report the impairment of serum GH responsiveness (GH baseline values: 0.2-1.9 ng/ml) to the administration of oral 150 microg clonidine [peak 4.7 ng/ml, normal values (nv)>10 ng/ml] and oral 4 mg dexamethasone (8.1 ng/ml, nv>10 ng/ml). Moreover, the evaluation of spontaneous 24-h GH secretion (Carmeda AB, Stockholm, Sweden) showed low mean GH levels (1.75 ng/ml, nv>3.0 ng/ml), with a maximum sleep-related peak of 2.8 ng/ml. Serum IGF-1 values were in the low-normal range (80-176 ng/ml, nv 133-626 ng/ml). While in FHS the cranio-facial features minimize with advancement of age, the impairment of growth velocity is permanent and results in severe dwarfism. In our case, treatment with recombinant GH (0.10 U/kg/day), administered by a needle-free device, induced a dramatic increase of growth velocity, increasing the height from -2.8 to -1.9 SD after 18 months, thus indirectly confirming a role of GH deficiency in the pathogenesis of FHS dwarfism.

Abnormalities, Multiple↗
PubMed2006

The neurobiology of Williams syndrome: cascading influences of visual system impairment?

Williams syndrome (WS) is characterized by a unique pattern of cognitive, behavioral, and neurobiological findings that stem from a microdeletion of genes on chromosome 7. Visuospatial ability is particularly affected in WS and neurobiological studies of WS demonstrate atypical function and structure in posterior parietal, thalamic, and cerebellar regions that are important for performing space-based actions. This review summarizes the neurobiological findings in WS, and, based on these findings, we suggest that people with WS have a primary impairment in neural systems that support the performance of space-based actions. We also examine the question of whether impaired development of visual systems could affect the development of atypical social-emotional and language function in people with WS. Finally, we propose developmental explanations for the visual system impairments in WS. While hemizygosity for the transcription factor II-I gene family probably affects the development of visual systems, we also suggest that Lim-kinase 1 hemizygosity exacerbates the impairments in performing space-based actions.

Brain↗
PubMed2003

[DiGeorge syndrome/velcardiofacial syndrome: oral and maxillofacial surgery].

The DiGeorge syndrome/velocardiofacial syndrome is the most frequent chromosomal microdeletion syndrome. Partial deletion of chromosome 22q11 may lead to symptoms including facial dysmorphy, hypoparathyroidism, thymic aplasia, congenital heart disease, developmental retardation, and disturbance of speech development. According to the literature, 9% of patients have cleft palate, an additional 5% have a submucosal cleft, and a total of 32% show velopharyngeal insufficiency. We studied 64 children with a cleft, or with delayed speech development and a submucosal or occult cleft, for the presence of the 22q11deletion using fluorescent in situ hybridisation. Five patients had the 22q11 deletion. We conclude that patients presenting with nasal speech and additional anomalies should all be studied for the presence of submucosal or occult clefting and for the presence of the DiGeorge syndrome/velocardiofacial syndrome.

Adolescent↗
PubMed2003

Development of NF2 gene specific, strictly sequence defined diagnostic microarray for deletion detection.

Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer syndrome caused by the biallelic inactivation of the neurofibromin 2 tumor suppressor gene ( NF2). Current molecular diagnostic methods for NF2 involve the detection of point mutations and/or microdeletions across the 100-kb locus from 22q12. Despite the fact that NF2 gene inactivating deletions occur in 25-30% of NF2 patients, the available approaches for high-resolution and high-throughput detection of deletions are underdeveloped. This need for improved methodology for gene copy number analysis is especially apparent when compared to a variety of methods available for accurate detection of point mutations. The microarray-based form of comparative genomic hybridization has been previously applied in the high-resolution analysis of gene copy number variation across large genomic regions. In this study we apply a PCR-based, strictly sequence-defined, repeat-free approach for the preparation of a diagnostic microarray for the detection of disease-causing deletions in the NF2 gene. The methodology is based on the preselection of target DNA by excluding redundant sequence within the NF2 locus using bioinformatics. This approach allows a significant increase in the resolution of deletion detection. The current average resolution of analysis across the NF2 locus is 23 kb. Therefore this NF2 gene-specific microarray is the first high-resolution tool for detection of diagnostically significant gene copy number aberrations. This microarray should now be applied in the analysis of an extensive series of NF2 patients, and hence we would like to call for such samples.

Base Sequence↗
PubMed1996

Spinal muscular atrophies: recent insights and impact on molecular diagnosis.

Spinal muscular atrophies (SMA) are a group of motor neuron diseases characterized by degeneration of anterior horn cells of the spinal cord and by muscular atrophy. Childhood-onset SMA is one of the most frequent autosomal recessive diseases and a leading cause of infant mortality. The underlying biochemical defect of SMA is unknown. Recently two genes have been isolated from the critical region at 5q13, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitor protein (NAIP) gene. Both genes are frequently deleted in SMA patients. NAIP is deleted in at least 45% of severely affected patients but less frequently in the milder forms. Homozygous deletions of exon 7 of SMN are found in approximately 95% of patients independently of clinical severity. A few point mutations and microdeletions in SMN have also been reported. This high frequency of deletions makes SMN analysis an important molecular diagnostic tool for childhood-onset SMA and greatly facilitates prenatal diagnosis. SMN analysis has also proven useful for the diagnosis of adult-onset SMA and variant forms. Although questions such as phenotype-genotype correlation must still be solved, the isolation of SMN and adjacent genes constitutes an important step towards the understanding of the molecular basis of the disease.

Chromosomes, Human, Pair 5↗
PubMed2006

A child with chromosome 22q11.2 deletion syndrome and a bilobed gallbladder.

We present an 11-year-old girl with a chromosome 22q11.2 microdeletion, velocardiofacial syndrome (VCFS), and a bilobed gallbladder as an incidental finding on abdominal sonography. The finding was confirmed by magnetic resonance cholangiopancreatography (MRCP). This is the first report of a gallbladder anomaly associated with a chromosome 22q11.2 deletion and the second report of a biliary tract anomaly associated with a mutation in the chromosome 22q11 region. We suggest that close attention be paid to the anatomy of the biliary tree in patients with mutations in the chromosome 22q11 region. Further study is warranted to determine the range and prevalence of biliary tract anomalies in this population.

Child↗
PubMed1999

Punctate epiphyses associated with Turner syndrome.

The radiographic observation of stippled calcification in cartilage defines the chondrodysplasia punctata group of bone dysplasias. Several other diseases may be associated with the radiographic finding of punctate epiphyses, usually uncommonly - for example, trisomy 21. Other more subtle chromosomal abnormalities also associated with punctate epiphyses include microdeletions of the X chromosome. A case of Turner syndrome with punctate calcification of the epiphyses is described.

Adult↗
PubMed2001

A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome.

The mouse scurfy gene, Foxp3, and its human orthologue, FOXP3, which maps to Xp11.23-Xq13.3, were recently identified by positional cloning. Point mutations and microdeletions of the FOXP3 gene were found in the affected members of eight of nine families with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked; OMIM 304930). We evaluated a pedigree with clinically typical IPEX in which mutations of the coding exons of FOXP3 were not detected. Our reevaluation of this pedigree identified an A-->G transition within the first polyadenylation signal (AAUAAA-->AAUGAA) after the stop codon. The next polyadenylation signal is not encountered for a further 5.1 kb. This transition was not detected in over 212 normal individuals (approximately 318 X chromosomes), excluding the possibility of a rare polymorphism. We suggest that this mutation is causal of IPEX in this family by a mechanism of nonspecific degradation of the FOXP3 gene message.

Cells, Cultured↗
PubMed2000

Genetic aspects of male infertility.

Genetic factors affecting male infertility are reviewed. Male infertility is classified under four general causes: spermatogenic disorder, obstruction of the seminal tract, inflammation, sexual disorders. Idiopathic spermatogenic disorder accounts for more than 50% of all of them. The cause of spermatogenic disorder is not yet identified. In recent years it has become obvious that some of the crucial genes expressed during male germ cell differentiation exist on the long arm of Y chromosome (Yq). Identification of a gene specifically involved in sperm production could provide a more rational basis for the treatment of male infertility. In this paper I review the history of azoospermia factor (AZF), which is involved in sperm production, and describe our research on a novel AZF candidate. In 1993 Ma and coworkers isolated an AZF candidate named YRRM; and in 1995 Reijo and coworkers reported another AZF candidate known as DAZ. The existence of additional genes on Yq is strongly suspected. We are now seeking a novel AZF candidate using positional cloning and an exon trapping method. The candidate should be included in the YAC yOX21 covering microdeleted portion of Yq found by analyzing DNA obtained from many infertile men. Several unknown sequences were identified by the analysis. Ongoing studies on AZF will prove useful in the diagnosis and treatment of male infertility.

Humans↗
PubMed2000

Comparative genomic sequence analysis of the Williams syndrome region (LIMK1-RFC2) of human chromosome 7q11.23.

Williams syndrome (WS) is a complex neurodevelopmental disorder arising from a microdeletion at Chr band 7q11.23, which results in a hemizygous condition for a number of genes. Within this region we have completely characterized 200 kb containing the genes LIMK1, WBSCR1, and RFC2. Evidence was also found for WBSCR5 in this region, but not the previously proposed genes WSCR2 and WSCR6. The syntenic region in mouse was also sequenced (115 kb) and characterized, and a comparative sequence analysis with a percent identity plot (PIP) easily allowed us to identify coding exons. This genomic region is GC rich (50.1% human, 49.9% mouse) and contains an unusually high abundance of repetitive elements consisting primarily of Alu (45.4%, one of the highest levels identified to date) in human, and the B family of SINES (30.6% of the total sequence) in mouse. WBSCR1 corresponds to eukaryotic initiation factor 4H, identified in rabbit, and is herein found to be constitutively expressed in both human and mouse, with two RNA and protein products formed (exon 5 is alternatively spliced). The transcription pattern of WBSCR5 was also examined and discussed along with its putative amino acid sequence.

Amino Acid Sequence↗
PubMed2000

Penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, and developmental delay: definition of a new clinical syndrome.

We describe a 2-month-old boy with penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect.

Abnormalities, Multiple↗
PubMed2000

Multiplex FISH and three-dimensional DNA imaging with near infrared femtosecond laser pulses.

We report on a novel technology for multicolor gene and chromosome detection as well as for three-dimensional (3D) DNA imaging by multiphoton excitation of multiple FISH fluorophores and DNA stains. Near infrared femtosecond laser pulses at 770 nm were used to simultaneously excite the visible fluorescence of a wide range of FISH fluorophores, such as FITC, DAC, Cy3, Cy5, Cy5.5, rhodamine, spectrum aqua, spectrum green, spectrum orange, Jenfluor, and Texas red as well as of DNA/chromosome stains, for example Hoechst 33342, DAPI, SYBR green, propidium iodide, ethidium homodimer, and Giemsa. In addition to the advantage of using only one excitation wavelength for a variety of fluorophores, multiphoton excitation provided the intrinsic possibility of 3D fluorescence imaging. The technology has been used in human genetics for the diagnosis of numerical chromosome aberrations and microdeletions. In particular, multicolor 3D images of the intranuclear localization of FISH-labeled chromosome territories in interphase nuclei of amniotic fluid cells have been obtained. Using the high light penetration depth at 770 nm, optical sectioning of Hoechst 33342-labeled DNA within living culture cells and within tissue of living tumor-bearing mice was performed.

Adult↗
PubMed2002

INK4a-ARF alterations and p53 mutations in primary and consecutive squamous cell carcinoma of the head and neck.

BACKGROUND: The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14(ARF) and p16(INK4a), that play active roles in the p53 and Rb tumor suppressive pathways, respectively. We analyzed the alterations of p14(ARF), p16(INK4a) and p53 to study the contribution of each pathway in tumorigenesis of 29 patients with primary and consecutive (second primary) squamous cell carcinoma of the head and neck (HNSCC), with a total of 68 carcinomas. METHODS: After microdissection, the DNA of 29 primary and 39 consecutive squamous cell carcinomas was analyzed for INK4a-ARF inactivation and p53 mutation by means of DNA sequence analysis, methylation-specific polymerase chain reaction (MSP), restriction-enzyme-related polymerase chain reaction (RE-PCR), multiplex RT-PCR and immunohistochemistry. In addition, microdeletions of p14(ARF) and p16(INK4a) were assessed using differential PCR. RESULTS: Altogether inactivation (methylation, loss of heterozygosity and mutation of exon 1beta) of p14(ARF) was found in 29 of all 68 (43%) carcinomas, with a significant difference in primary [8 of 29 (28%)] relative to second primary carcinomas [21 of 39 (54%)]. Methylation of p16(INK4a) occurred in 22 of 68 (32%) carcinomas with an even distribution among primary and consecutive tumors. Only two (secondary) carcinomas showed simultaneous promoter methylation of p14(ARF) and p16 (INK4a). Mutations of p53 were found in 32 of 68 HNSCCs (44%), evenly distributed among primary and recurrent carcinomas. p14(ARF) alterations showed no relationship to p53 mutations. CONCLUSIONS: Our data indicate that the INK4a-ARF-/p53 pathway was disrupted in 58 of 68 (84%) primary and recurrent tumors, either by p53 mutations or by INK4a-ARF inactivation. p14(ARF) methylation occurred independently of p16(INK4a) alterations and showed no correlation to p53 mutations. The significantly higher rate of p14(ARF) alterations in recurrent (respective second primary) carcinomas suggests a further acquired genetic aberration during the development of the recurrent carcinomas.

Biomarkers, Tumor↗