Upstream open reading frames regulate translation of the long isoform of SLAMF1 mRNA that encodes costimulatory receptor CD150.

More than 40% of human genes contain upstream open reading frames (uORF) in their 5'-untranslated regions (5'-UTRs) and at the same time express at least one truncated mRNA isoform containing no uORF. We studied translational regulation by four uORFs found in the 5'-UTR of full-length mRNA for SLAMF1, the gene encoding CD150 membrane protein. CD150 is a member of the CD2 superfamily, a costimulatory lymphocyte receptor, a receptor for measles virus, and a microbial sensor on macrophages. The SLAMF1 gene produces at least two mRNA isoforms that differ in their 5'-UTRs. In the long isoform of the SLAMF1 mRNA that harbors four uORFs in the 5'-UTR, the stop codon of uORF4 overlaps with the AUG codon of the main ORF forming a potential termination-reinitiation site UGAUG, while uORF2 and uORF3 start codons flank a sequence identical to Motif 1 from the TURBS regulatory element. TURBS was shown to be required for a coupled termination-reinitiation event during translation of polycistronic RNAs of some viruses. In a model cell system, reporter mRNA based on the 5'-UTR of SLAMF1 short isoform, which lacks any uORF, is translated 5-6 times more efficiently than the mRNA with 5'-UTR from the long isoform. Nucleotide substitutions disrupting start codons in either uORF2-4 result in significant increase in translation efficiency, while substitution of two nucleotides in TURBS Motif 1 leads to a 2-fold decrease in activity. These data suggest that TURBS-like elements can serve for translation control of certain cellular mRNAs containing uORFs.

Phenotypic variability in Patau syndrome.

UNLABELLED: Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13. MATERIAL AND METHODS: The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre. RESULTS: Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case. CONCLUSIONS: Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality.

[Array CGH: technical considerations and applications]. / Hibridizarea genomica comparativa pe microretele: consideratii tehnice si aplicatii.

During the past ten years a particular molecular technology - array comparative genomic hybridization (aCGH)--has received a great deal of attention. Array CGH can detect simultaneously sub-microscopic copy number changes across the whole genome, thus overcoming the limitations of karyotyping or locus-specific techniques. Array CGH has become an important tool for clinical diagnostics and gene-identification studies and is having a great impact on the understanding of pathologies, the counselling of families and patient management. Different types of array CGH platforms at increasingly higher resolution have been developed, differing mainly in the type of the interrogating probes and in their coverage of the genome. Here, we review the array CGH methodology and its various applications in clinical diagnostics and research. Although it's an expensive technology and differentiating between pathogenic and benign copy number variations is a challenging task, array CGH is an efficient and robust method for assesing disease-causing genomic imbalances and will probably replace karyotype as the primary cytogenetic test.

Ring autosomes: some unexpected findings.

Ring chromosomes are rare entities, usually associated with phenotypic abnormalities in correlation with the loss of genetic material. There are various breakpoints and sometimes there is a dynamic mosaicism that is reflected in clinical features. Most of the ring chromosomes are de novo occurrences. Our study reflects the experience of three Romanian cytogenetic laboratories in the field of ring chromosomes. We present six cases with ring chromosomes involving chromosomes 5, 13, 18, and 21. All ring chromosomes were identified after birth in children with plurimalformative syndromes. The ring chromosome was present in mosaic form in three cases, and this feature reflects the ring's instability. In case of ring chromosome 5, we report a possible association with oculo-auriculo-vertebral spectrum.

[Improvement of genetic diagnostic strategy in velo-cardio-facial syndrome]. / Optimizarea strategiei de diagnostic genetic în sindromul velo-cardio-facial.

UNLABELLED: Velo-Cardio-Facial Syndrome (VCFS) is characterized by congenital heart defects (CHD), palatal abnormalities, facial dysmorphism, neonatal hypocalcemia, immune deficit, speech and learning disabilities. SVCF is caused by microdeletion 22q11.2. Microdeletion is detected by fluorescence in situ hybridization (FISH). The highly variable phenotype makes diagnosis and selection for FISH more difficult. AIM: To retrospectively analyze and compare the phenotype of children with a clinical diagnosis of VCFS with/without 22q11 deletion; to verify the validity of literature guidelines and to describe combinations of clinical features that should lead to molecular analysis. MATERIAL AND METHODS: The present study was performed in 21 patients with a clinical diagnosis of VCFS. Methaphase chromosome spreads were prepared from phytohaemagglutinin stimulated lymphocyte culture by standard methods before FISH. The patients were divided into two groups according to FISH test: positive and negative. RESULTS: The features commonly noticed in FISH positive patients were: palatal abnormalities/hypernasal speech, learning disabilities, facial dysmorphism, tapered fingers (6/6), CHD (5/6) and recurrent infections (2/6). In FISH negative patients the following were found: learning disabilities, CHD (12/15); facial dysmorphism (10/15), family history of CHD (7/15), short stature (6/15), hypocalcemia, tapered fingers (5/15), recurrent infections (3/15) and palatal cleft (2/15). In both groups, Tobias and McDonald-McGinn guidelines were positive. CONCLUSIONS: VCFS has a highly variable phenotype. Our study suggests that 22q11.2 deletion analysis by FISH should be performed in patients who have at least 2 (newborn)/3 (child, adult) specific criteria: CHD, hypocalcemia, palatal abnormalities, facial dysmorphism, learning disabilities, digital anomalies, and immune deficit.

Epigenetic regulation of neurogenesis in the adult hippocampus.

The dentate gyrus of the hippocampus is an exception to a 'neurogenesis-unfriendly' environment of the adult brain. New functional neurons generated in this region contribute to learning and mood regulation, and thus represent a unique form of neural plasticity. The rate of hippocampal neurogenesis significantly changes on physiological or pathological influences, such as physical activity, environmental enrichment, stress, and aging. We suggest that epigenetic mechanisms could be sensors of environmental changes and fine modulators of adult hippocampal neurogenesis. Here, we examine the role of DNA methylation and methylation of core histones mediated by the Polycomb and Trithorax complexes in the regulation of adult neurogenesis. Given the recent surprising discovery of dynamic and reversible DNA methylation in the hippocampus, we speculate regarding its regulation and its role in adult neurogenesis.

Hereditary hemochromatosis in north-eastern Romania.

UNLABELLED: Hereditary hemochromatosis is a genetic disturbance of iron metabolism resulting in iron overload in several organs and their functional failure. Early diagnosis is necessary to start a simple and effective therapy: bleeding. It is the most frequent genetic disease in some populations. Our objectives were 1. An estimate of the expectancy of the disease in the population of our geographic region, and 2. To diagnose the disease by applying the established methods and estimate the efficiency of our diagnosis. METHODS: 1.To estimate the expectancy, we genotyped 200 persons for the most frequent mutations causing the disease: HFE-C282Y and HFE-H63D by PCR-RFLP. 2. To diagnose the disease phenotypically we determined plasma iron level, ferritin level and transferrin saturation index in 549 patients previously diagnosed as chronic hepatitis or cirrhosis and genotyped those with hemochromatosis phenotype. RESULTS: 1. We found allelic frequencies of 1.75% and 13.25% for the HFE-C282Y and H63D mutant alleles respectively. From these frequencies we calculated that a severe case caused by a C282Y/C282Y homozygote can arise in 816 people and a mild case caused by a C282Y/H63D compound heterozygote can arise in 100 people 2. Among 549 patients we found 10 to have the phenotype of hemochromatosis and 3 out of the 10 were found to carry mutations: two in the HFE gene (one homozygous C282Y and one compound heterozygous C282Y/H63D) and one in the hemojuvelin (HJV) gene (a G320V).

[Chromosomal evaluation in couples with reproductive disorders--retrospective study of a selected group of 266 couples]. / Evaluarea cromozomiala a cuplurilor cu tulburari de reproducere--studiu retrospectiv pe un lot selectionat de 266 cupluri.

UNLABELLED: Reproductive Disorders (RD), manifested by the biological inability to conceive (primary sterility) or inability to carry a pregnancy to full-term (infertility), affect 10-15% of reproductive-aged couples. The genetic etiology of RD is represented, in the majority of cases, by the chromosomal abnormalities. AIM: To retrospectively analyze the karyotype results in a selected group of couples with RD. MATERIAL AND METHOD: The present study was performed in 266 couples with RD: 80 (30.07%) with primary sterility (ST), 149 (56.01%) with Recurrent Spontaneous Abortions (RSA) and 37 (13.90%) with Stillborn Children (SC). A GTG-banded karyotype was performed on both partners of each couple. RESULTS: We identified a chromosomal abnormality in 43 individuals (16.16%): 20 cases (7.51%) with ST, 13 cases (4.88%) with RSA and 10 cases (3.75%) with SC. The affected partner was female in 23 cases (8.64%) and male in 20 cases (7.51%). A X chromosome (numerical or structural) abnormality was detected in 18 cases (6.76%), most frequent X chromosome monosomy mosaicism in female and trisomy XXY in male; a balanced structural chromosomal abnormality (BSC) was detected in 23 couples (8.64%); in other two males with ST, the karyotype result was 46,XX. CONCLUSIONS: The results of our study are similar to other reported studies and underline the major etiologic role of chromosomal abnormalities in RD and the importance of chromosomal analysis for the etiologic diagnosis and genetic counseling of these patients.

[Recent advances in molecular pathogenesis and polycystic kidney disease treatment]. / Progrese recente în patogenia moleculara si în tratamentul bolilor renale polichistice.

Polycystic kidney diseases (PKD) are common genetic disorders characterized by formation and progressive enlargement of cysts kidney, liver and other organs, leading to end stage renal disease. Regardless of the genetic defect underlying PKD, cystic epithelia seem to display common abnormalities: increased proliferation and apoptosis, loss of cellular differentiation and polarity, hypersecretion. The localization of multiples proteins, whose function are disrupted in PKD, in the primary cilium or at basal body at the base of the cilium highlight this neglected organelle as a common trigger of cystic diseases. Significant progresses have been made over the last few years towards a greater understanding of the molecular pathogenesis of cysts formation, particularly in the signaling pathways involved in cytogenesis: cAMP, mTOR, Wnt, Ras/MAPK. These advances have already brought several potential therapies targeting several key pathways of cystogenesis.

[Idiopathic mental retardation--importance of clinical diagnostic scores for case selection]. / Retardul mental idiopatic--importanta scorurilor de diagnostic clinic pentru selectia cazurilor.

We present a retrospective study aimed to identify the correlation between de Vries clinical score and the detection of chromosomal abnormalities in mentally retarded (MR) children. We have used the score to identify patients who should be tested by karyotyping and subsequently MLPA (multiplex ligation dependent probe amplification) for subtelomeric rearrangements. Our group is formed of 36 children with variable MR associated with other anomalies. 18 children had chromosomal defects, whereas 18 had normal karyotypes. In the first group, total scores varied between 3 and 7. Chromosomal anomalies identified were: numerical (4) and structural (14). Chromosomes involved were: 1, 4, 5, 7, 8, 9, 17, X. Deletions were the most common and correlate with a greater score (> or = 4). Common clinical features were: short stature, microcephaly, nasal, ear and hand anomalies. In the second group the most frequent clinical feature was hand anomaly (61.2%) and cases with a high score have to be further tested (e.g. using MLPA) in order to identify minor defects. In our opinion a high score indicates the karyotype and then a MLPA testing. In conclusion, we present a retrospective study that proves the use of de Vries diagnostic score in the identification of chromosomal abnormalities in MR children.

[Recent advances in molecular pathogenesis and treatment of polycystic kidney disease]. / Progrese recente în patogenia moleculara si în tratamentul bolilor renale polichistice.

Polycystic kidney diseases (PKD) are common genetic disorders characterized by formation and progressive enlargement of cysts kidney, liver and other organs, leading to end stage renal disease. Regardless of the genetic defect underlying PKD, cystic epithelia seem to display common abnormalities: increased proliferation and apoptosis, loss of cellular differentiation and polarity, hypersecretion. The localization of multiples proteins, whose function are disrupted in PKD, in the primary cilium or at basal body at the base of the cilium highlight this neglected organelle as a common trigger of cystic diseases. Significant progresses have been made over the last few years towards a greater understanding of the molecular pathogenesis of cysts formation, particularly in the signaling pathways involved in cytogenesis: cAMP, mTOR, Wnt, Ras/MAPK. These advances have already brought several potential therapies targeting several key pathways of cystogenesis.

[Clinical, epidemiological and cytogenetic studies on 221 patients with Down syndrome]. / Studii clinice, epidemiologice si citogenetice pe un lot de 221 pacienti cu sindrom Down.

UNLABELLED: Down syndrome, determined by 21 trisomy, represents a major cause of infantile morbidity and mortality. AIM: The analysis of dysmorphic features in Down syndrome, incidence of major congenital abnormalities, of some epidemiological parameters and cytogenetic specifics. MATERIAL AND METHOD: Methods used were clinical, epidemiological and cytogenetical. We analysed 221 patients, from Iasi county, with clinical supposition of Down syndrome, identified in the first year of life, between 1985 and 1999. RESULTS: The majority of patients (67%) have more than 5 from 10 characteristics dysmorphic signs of Down syndrome in neonatal period. Visceral congenital abnormalities--82 cases (37.1%) were isolate (cardiac or digestive) or multiple. The presence of one visceral abnormality determined the death of patient in 30 cases (46.15% of death). Medium incidence of Down syndrome in Iasi county was 1.306 per thousand (1/769 new-born), with median value 1.091per thousand and corrected value related to the maternal age 1.056 per thousand. Cytogenetic analysis was performed at 101 patients, in 95 cases (94.05%) clinical suspicion of Down syndrome was correct, patients presenting 21 trisomy (in the majority of cases a homogenous free trisomy). CONCLUSION: The data obtained by us are concordant with the majority of literature studies, that a test the correctness of clinical trial and validate our results.

[Considerations regarding one particular case of Rett syndrome]. / Discutii pe marginea unui caz particular de sindrom Rett.

Rett syndrome is a form of X-linked mental retardation limited to females, expressed by postnatal microcephaly, moderate/severe mental retardation and prominent autistic features. We present a case to illustrate this rare entity, but also to discuss the suggestive behaviour and to underline the importance of diagnostic criteria. Our case associates porencephaly and positive CMV test that raised diagnostic difficulties in the beginning.

[Importance of genetic factors in the pathogenesis of gonadal and postgonadal human infertility]. / Importanta factorilor genetici în patogenia sterilitatii umane periferice (gonadica si postgonadica).

The infertility is a important health problem, affecting about 10-15% of couples. The important role of genetic factors in pathogenesis of infertility is now increasingly recognized and our knowledge in this field are improved each day. For these reasons we review the most important genetic causes of infertility. In this paper we analyse the genetic implications in gonadal and postgonadal infertility. Gonadal infertility affects both sexes and are characterised by hypergonadotrophic hypogonadism. Gonadal infertility is produced by chromosomal or monogenic mutations. Chromosomal causes are represented by gonosomal aneuploidy and structural chromosomal abnormalities. The monogenic disorders are consequences of a recessive mutations of hormone, hormonal receptor or enzymes genes. Postgonadal infertility is present in men and is the result of some obstructive disorders.

[ The importance of genetic factors in pathogenesis of central infertility (hypothalamic and pituitary]. / Importanta factorilor genetici în patogenia sterilitatii umane centrale (hipotalamica si hipofizara).

The infertility is a important health problem, affecting about 10-15% of couples. The important role of genetic factors in pathogenesis of infertility is now increasingly recognized and our knowledges in this field are improved each day. For these reasons we review the most important genetic causes of infertility. In this paper we analyse the genetic implications in central infertility (hypothalamic and pituitary). These conditions affect both sexes and are characterised by hypogonadotrophic hypogonadism. In majority of cases central infertility is produced by recessive mutations of hormone or hormonal receptor genes. In some cases the infertility is a component of a specific syndrome.

Successful renal transplantation decreases aortic stiffness and increases vascular reactivity in dialysis patients.

BACKGROUND: Patients with end-stage renal disease on dialysis have among the highest cardiovascular event rates documented. Abnormal nitric oxide (NO)-dependent endothelial reactivity and increased arterial stiffness are commonly described in hemodialysis (HD) patients. Measures of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AGI)--have been shown to be powerful predictors of survival on hemodialysis. It is not known how these parameters interfere with successful renal transplantation. METHODS: PWV and aortic AGI (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 41 HD patients (20 men; age, 41.8 years) and in a control group of 20 patients with essential hypertension (HTA) (10 men; age, 43.6 years). Twenty of the HD patients (10 men; age, 39.7 years) received live-related renal transplants (RTx) and were restudied (3 months after RTx, normal serum creatinine). NO-dependent and NO-independent vascular reactivity were assessed by changes in AGI after challenges with inhaled salbutamol (SAL) and sublingual nitroglycerin (NTG), respectively. RESULTS: AGI values were significantly lower in RTx patients compared with subjects on hemodialysis (15.9 +/- 13.9% vs. 27.9 +/- 11.9%, P<0.05), but similar to essential HTA controls (16.5 +/- 17%). Serial AGI measurements showed that successful renal transplantation is associated with a decrease in AGI in all cases, from a mean of 25.1 +/- 7.8% while on dialysis to 15.9 +/- 7.0% 3 months after transplantation (P<0.0001). The responsiveness to both endothelium-dependent stimuli (inhaled SAL) and endothelium-independent stimuli (sublingual NTG) was greater in transplant patients than in hemodialysis patients (SAL-induced decrease in AGI -82.3 +/- 65.7% vs. 45 +/- 72.3%, P<0.01; and NTG-induced decrease in AGI 197 +/- 108 vs. -129.0 +/- 215.5%, P<0.01). PWV values in dialysis patients (7.19 +/- 1.88 m/sec) were significantly higher than those measured in essential HTA patients (6.34 +/- 1.32 m/sec, P<0.05) with normal renal function (despite similar blood pressure levels). PWV after RTx was 6.59 +/- 1.62 m/sec, significantly different from pretransplantation (dialysis) values (P<0.05 for comparison) but similar to the control group of essential HTA patients. CONCLUSIONS: Renal transplantation is associated with marked improvements in vascular structure and function to a profile comparable to essential HTA patients.

[DNA repair pathways and their involvement in human diseases]. / Mecanismele de reparare a leziunilor ADN. Implicatii în patologia umana.

Integrity maintenance of the genome is crucial. Human DNA is vulnerable to damage arising from both endogenous and exogenous sources. Different DNA repair pathways counteract these potentially mutagenic accidents: damage reversal by methylguanine methyl transferase (MGMT), base nucleotide repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and repair of strand breaks. In some cases, DNA damage is not repaired but is instead bypassed by specialized DNA polymerases. The existence of human diseases associated with defects in DNA repair illustrates the importance of this process of quality control. Many of these human diseases have an increased susceptibility to cancer.

[Osler--Rendu Disease: an example of a family clustering in a genetic disorder]. / Maladia rendu-osler: exemplu de agregare familiala a unei boli genetice.

The case of a 75 years old woman with hereditary hemorrhagic telangiectasia (HHT) is presented. This condition is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a "triad" of telangiectasia, recurrent epistaxis and a family history of the disorder.

[2 cases of Lowe syndrome]. / Doua cazuri de sindrom Löwe.

Löwe syndrome is a form of X-linked mental retardation with short stature, cataracts, renal tubular dysfunction and hypotonia. We present 2 cases to illustrate this rare entity, but also to discuss the suggestive aspect of the face and to underline the importance of molecular tests for genetic counselling. Both cases associate ocular, cerebral and renal defects. Molecular tests changed the recurrence risk in the first family.