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PubMed1993

Interphase molecular cytogenetic analysis of epithelial ovarian carcinomas.

Karyotype information on ovarian carcinomas has been limited because the tumors are often difficult to culture and the resultant metaphases can have complex numerical and structural chromosomal anomalies. Fluorescent in situ hybridization is a rapid method of determining centromere copy number in metaphase cells and interphase nuclei. Fluorescent in situ hybridization was used to determine the numerical centromere complement of chromosomes X, 8, 12, and 17 and HER-2/neu gene amplification within interphase nuclei of 25 primary epithelial ovarian carcinomas. Touch preparations of the carcinomas were hybridized with two-color combinations of directly labeled alpha-satellite centromeric chromosome enumeration probes and a directly labeled HER-2/neu probe. Modal centromere copy numbers for each of the four chromosomes were used to determine numerical abnormalities relative to the flow cytometric DNA ploidy level for each tumor. Four cases were found to be normal with respect to the four chromosomes studied. In the remaining 21 cases a relative loss of chromosomes 17 (16 cases) and X (nine cases) and a relative gain of chromosomes 12 (10 cases) and 8 (nine cases) were the most common findings. In addition, the HER-2/neu gene was amplified in two of the 25 tumors. In conclusion, fluorescent in situ hybridization is an excellent method for rapid determination of numerical abnormalities and gene amplification in ovarian carcinomas.

Biomarkers, Tumor↗
PubMed2002

Visualization of replication initiation and elongation in Drosophila.

Chorion gene amplification in the ovaries of Drosophila melanogaster is a powerful system for the study of metazoan DNA replication in vivo. Using a combination of high-resolution confocal and deconvolution microscopy and quantitative realtime PCR, we found that initiation and elongation occur during separate developmental stages, thus permitting analysis of these two phases of replication in vivo. Bromodeoxyuridine, origin recognition complex, and the elongation factors minichromosome maintenance proteins (MCM)2-7 and proliferating cell nuclear antigen were precisely localized, and the DNA copy number along the third chromosome chorion amplicon was quantified during multiple developmental stages. These studies revealed that initiation takes place during stages 10B and 11 of egg chamber development, whereas only elongation of existing replication forks occurs during egg chamber stages 12 and 13. The ability to distinguish initiation from elongation makes this an outstanding model to decipher the roles of various replication factors during metazoan DNA replication. We utilized this system to demonstrate that the pre-replication complex component, double-parked protein/cell division cycle 10-dependent transcript 1, is not only necessary for proper MCM2-7 localization, but, unexpectedly, is present during elongation.

Animals↗
PubMed2006

Identification of limited regions of genetic aberrations in patients affected with Wilms' tumor using a tiling-path chromosome 22 array.

Wilms' tumor (WT) is one of the most common solid tumors of childhood. The genetics of this disorder is complex and few studies have suggested allelic loss of chromosome 22 as a frequent aberration. To assess tumor- and possible germline-specific regions affected with gene copy number variations on this chromosome, we applied a high-resolution genomic clone-based chromosome 22 array to a series of 28 WT samples and the paired blood-derived DNA of the patients. The group of tumors was enriched for cases with metastases, relapse or fatal outcome, criteria that were expected to yield a higher number of alterations on chromosome 22. Overall, the array-based form of comparative genomic hybridization (array-CGH) analysis revealed genomic changes in 53% (15 out of 28) of cases. We identified hemizygous deletion of the whole arm of 22q in 3 tumors (11%). Furthermore, a complex amplifier genotype was detected in 8 samples, presenting regions of gain along the chromosome, which defined 7 distinct minimal overlapping segments. The distribution of aberrations in 4 additional cases displaying regional genomic imbalances delimited 2 tumor suppressor/oncogene candidate loci, 1 in the proximal and the other in the terminal part of 22q. Analysis of these regions revealed the presence of several candidate genes that may play a role in the development of WT. These findings demonstrate the power of array-CGH in the determination of DNA copy number alterations and further strength the notion that WT-associated genes exist on this chromosome.

Child↗
PubMed1993

A small chromosome of Leishmania (Viannia) braziliensis contains multicopy sequences which are complex specific.

Orthogonal Field Alternating Gel Electrophoresis (OFAGE) has been used to show a band of approximately 260 kb which is stained intensely with ethidium bromide in Leishmania (V.) braziliensis stock M2903. This small chromosome (sc-2903), as well as a 50 kb and a 200 kb chromosome seen in L. (L.) mexicana and L. (L.) amazonensis, respectively, are stably maintained and linear. When used as a hybridisation probe, sc-2903 showed homology to large chromosomal DNA bands and to a multiplicity of genomic fragments in all braziliensis stocks tested, indicating either different sequences, different copy numbers or both but no hybridisation to mexicana stocks. It is possible that these sequences are present in all members of the braziliensis complex and are not related to LD1 or any other previously published small chromosome sequences. However, at least one clone isolated from a sc-2903 library recognised genomic DNA of stocks belonging to the braziliensis, mexicana and donovani complexes. Our results suggest that the clone carries sequence(s) that are repeated and shared between stocks of different complexes but with a variable genomic distribution.

Animals↗
PubMed2006

Gene copy number profiling of soft-tissue leiomyosarcomas by array-comparative genomic hybridization.

Leiomyosarcoma (LMS) is a rare malignant mesenchymal tumor of smooth muscle cells. Chromosomal aberrations in LMS have been studied, but the cytogenetic data that have been published so far are complex, limited, and incomplete. Here, we performed for the first time a high-resolution genome-wide array comparative genomic hybridization (CGH) analysis (aCGH) on a pool of 14 low- and high-grade LMS cases to obtain gene-level information about the amplified and deleted regions that may play a role in the development and progression of LMS. Our aCGH results indicated that 2,218 genes were involved in 25 altered chromosomal regions; 9 regions in low-grade LMS, 12 regions in high-grade LMS, and 4 minimal common regions shared by low- and high-grade LMS. The frequency of DNA copy number gains in high-grade LMS was threefold compared to low-grade LMS, whereas losses in low-grade LMS were almost twice as frequent as in high-grade LMS. Both low- and high-grade tumors shared two minimal common regions of gain (15q26 approximately qter and 17p13.1 approximately q11) and loss (6p12 approximately p21.3 and 13q14.3 approximately qter). Moreover, our findings indicated that low- and high-grade LMS and osteosarcoma share 12 genes located in the 17p amplicon. In conclusion, by using aCGH, we were able to define the precise location of the altered chromosomal areas and to identify putative tumor suppressor genes and oncogenes therein. The list of altered genes in the minimal common regions is available as at our web site (http://www.helsinki.fi/cmg/microarray_data).

Adult↗
PubMed1972

Effect of growth conditions on the formation of the relaxation complex of supercoiled ColE1 deoxyribonucleic acid and protein in Escherichia coli.

Colicinogenic factor E1 (ColE1) is present in Escherichia coli strain JC411 (ColE1) cells to the extent of about 24 copies per cell. This number does not appear to vary in situations which give rise to twofold differences in the amount of chromosomal deoxyribonucleic acid (DNA) present per cell. If cells are grown in the absence of glucose, approximately 80% of the ColE1 molecules can be isolated as strand-specific DNA-protein relaxation complexes. When glucose is present in the medium, only about 30% of the plasmid molecules can be isolated as relaxation complexes. Medium shift experiments in which glucose was removed from the medium indicate that within 15 min after the shift the majority (>60%) of the plasmid can be isolated as relaxation complex. This rapid shift to the complexed state is accompanied by a two- to threefold increase in the rate of plasmid replication. The burst of replication and the shift to the complexed state are both inhibited by the presence of chloramphenicol. Inhibition of protein synthesis in log cultures by the addition of chloramphenicol or amino acid starvation allows ColE1 DNA to continue replicating long after chromosomal replication has ceased. Under these conditions, noncomplexed plasmid DNA accumulates while the amount of DNA that can be isolated in the complexed state remains constant at the level that existed prior to treatment. In the presence of chloramphenicol, there appears to be a random dissociation and association of ColE1 DNA and "relaxation protein" during or between rounds of replication.

Bacterial Proteins↗
PubMed1987

Binding of the herpes simplex virus immediate-early gene product ICP4 to its own transcription start site.

A gel electrophoresis DNA-binding assay was used to detect proteins from herpes simplex virus type 1-infected and uninfected cells that specifically bind the upstream region of immediate-early (IE) gene 3. The assay is based on the altered electrophoretic mobility of DNA-protein complexes relative to that of free DNA in native gels. A series of end-labeled overlapping DNA fragments spanning a region from -272 to +27 (relative to the 5' terminus of the IE gene 3 mRNA) were used as probes. Two complexes were identified (referred to as A and B) which were driven by different protein factors. Formation of the A complex required infected-cell proteins extracted at any time from 2 to 16 h postinfection; a 0.5 to 1 M NaCl extract of infected cells, and a DNA probe that contained the sequences from -4 to +27 (relative to the 5' terminus of IE gene 3 mRNA). The protein that drove the formation of the A complex is not related to transcription factors TFIIIA or Sp1 or their cognate binding domains since neither the 5S RNA gene nor the GC box of simian virus 40 could compete for proteins that induced formation of the A complex. Through the use of monoclonal antibodies, the complex was shown to contain the IE gene 3 product, ICP4. A more detailed localization of the DNA-binding site in vitro by using chemical footprinting revealed that binding occurs over the sequence from -10 to +3 relative to the mRNA terminus. The binding of ICP4 to its own transcription start site may explain the repression of IE gene transcription which attends the onset of early (beta) gene expression and suggests an autoregulatory mechanism for gene control in herpes simplex virus type 1. The B complex was readily detected in uninfected cells (of a number of different cell lines), as well as in infected cells, with a probe containing the IE consensus sequence TAATGARATTC (where R is a purine) and two nested copies of the Sp1 binding motif GGGCGG; however, complexes were also detected with probes that lack the IE consensus sequence but contain Sp1 sites. These data suggest that the B complex contains the promoter-specific factor Sp1, and competition experiments with the clustered Sp1 binding domains from simian virus 40 confirmed this idea.

Binding Sites↗
PubMed1976

Effect of estrogen on gene expression in the chick oviduct. Effect of estrogen on the sequence and population complexity of chick oviduct poly(A)-containing RNA.

Total cellular RNA preparations were isolated from chicken oviducts at three different development stages: (a) immature chicks which were chronically stimulated with estrogen; (b) estrogen-stimulated chicks which were then withdrawn from hormone for 12 days; and (c) laying hens. Total cellular RNA containing 3'-poly(A) sequences (poly(A)-RNA) were than isolated from these preparations using oligo(dT)-cellulose chromatography. The number average nucleotide length of the poly(A)-RNA preparations in each case was approximately 2000 nucleotides. The number average nucleotide length of the poly(A) residues at the 3'-terminal end of each RNA preparation was approximately 70 adenylate residues. Complementary DNA (cDNA) copies to each preparation of poly(A)-RNA were synthesized using avian myeloblastosis virus RNA-directed DNA polymerase. The cDNApoly(A) preparations were then utilized in DNA excess hybridization experiments to analyze the complexity of the DNA sequences from which these RNAs were transcribed. Approximately 22% of each of the total cellular poly(A)-RNAs were transcribed from repeated DNA sequences (average repeat frequency of 35 copies/genome) while the remaining majority were transcribed from single copy or unique sequence DNA. It was possible to estimate the number of different poly(A)-RNA sequences per cell by analyzing the kinetics of hybridization of these cDNApoly(A) preparations to total cellular poly(A)-RNA extracts under conditions of RNA excess. The results revealed that 41% of the poly(A)-RNA from laying hen oviduct consisted of, on the average, three different sequences/cell, each of which was present in approximately 25,000 copies/cell. The remainder of the poly(A)-RNA in this tissue consisted of approximately 25,000 different sequences/cell, which were present largely in only two or three copies/cell. A somewhat similar sequence complexity was found for oviduct cells prepared from estrogen-stimulated chicks. We estimated that there were approximately 20,000 different poly(A)-RNA sequences/cell, each represented in only one to two copies/cell. However, there were five sequences which were present, on the average, in a concentration of 5600 copies/cell. The poly(A)-RNAs from hormone-wtihdrawn tissue, on the other hand, had a lower sequence complexity. There were only approximately 10,000 different poly(A)-RNA sequences/cell, each present in about three copies/cell. Furthermore, the few sequences present in a great abundance in hen and hormone-stimulated tissues were apparently absent in oviduct tissue from hormone-wtihdrawn chicks, suggesting that the intracellular concentrations of these high frequency RNA sequences are dependent on estrogen.

Animals↗
PubMed2006

Strategies for the detection of copy number and other structural variants in the human genome.

Advances in genome scanning technologies are revealing that copy number variants (CNVs) and polymorphisms, ranging from a few kilobases to several megabases in size, are present in genomes at frequencies much greater than previously known. Discoveries of additional forms of genomic variation, including inversions, insertions, deletions and complex rearrangements, are also occurring at an increased rate. Along with CNVs, these sequence alterations are collectively known as structural variants, and their discovery has had an immediate impact on the interpretation of basic research and clinical diagnostic data. This paper discusses different methods, experimental strategies and technologies that are currently available to study copy number variation and other structural variants in the human genome.

Gene Dosage↗
PubMed2007

Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1.

Resistance to the HER-2 targeting drug trastuzumab can be observed clinically, but the lack of suitable experimental models hampers studies of resistance mechanisms. We characterized a HER-2-positive carcinoma cell line (JIMT-1) derived from a 62-year-old breast cancer patient which was clinically resistant to trastuzumab. Multicolor fluorescence in situ hybridization revealed a complex hyperdiploid karyotype with numerous marker chromosomes and unbalanced translocations. Comparative genomic hybridization (CGH) revealed numerous regions of copy number aberration (CNA). Further analysis by array CGH identified 27 regions of CNA (16 amplified, 11 deleted). Thirty-eight percent of the genes in the amplified regions were overexpressed, compared to only 9% in regions of normal copy number ratios (CNR). Accordingly, 26% of the genes in the deleted regions were underexpressed, compared to 10% in regions of normal CNR. Most amplified and overexpressed genes were located on chromosome 1 as well as on 8q, 12q14.1, 17q11 approximately q21, and 20q13. In 17q11 approximately q21, we identified two separate amplicons, the HER-2 amplicon and a previously unreported amplicon at 17q21.31. Several aberrant genes are implicated in cancer development (e.g., JUN, CDK4, and SLUG protooncogenes, as well as the drug/hormone-metabolizing genes GSTM1 and CYP24). We conclude that cytogenetic and expression profiling of JIMT-1 revealed several new features that need further characterization and may shed light on trastuzumab resistance.

Animals↗
PubMed2005

Revealing the genomic heterogeneity of melanoma.

The melanoma genome possesses numerous recurrent chromosomal rearrangements, and embedded within this complexity are clues critical to disease pathogenesis and response to therapy. High-resolution genome-wide DNA copy number approaches, in conjunction with gene-specific mutational analyses, appear poised to define keystone molecular events, provide more accurate classification schemes, and set the stage for the design of rational therapies that may finally have an impact on survival of this deadly disease.

Alternative Splicing↗
PubMed2004

Sequencing the maize genome.

Sequencing of complex genomes can be accomplished by enriching shotgun libraries for genes. In maize, gene-enrichment by copy-number normalization (high C(0)t) and methylation filtration (MF) have been used to generate up to two-fold coverage of the gene-space with less than 1 million sequencing reads. Simulations using sequenced bacterial artificial chromosome (BAC) clones predict that 5x coverage of gene-rich regions, accompanied by less than 1x coverage of subclones from BAC contigs, will generate high-quality mapped sequence that meets the needs of geneticists while accommodating unusually high levels of structural polymorphism. By sequencing several inbred strains, we propose a strategy for capturing this polymorphism to investigate hybrid vigor or heterosis.

Chromosomes, Artificial, Bacterial↗
PubMed1989

P-glycoprotein gene amplification and expression in multidrug-resistant murine P388 and B16 cell lines.

P-glycoprotein gene (mdrl) amplification and expression were examined in murine leukaemia P388/DX and melanoma B16VDXR cell lines, which exhibit a high level of resistance to a selecting agent, doxorubicin, and express a multidrug-resistant phenotype because they are cross-resistant to multiple cytotoxic drugs. The multidrug-resistant phenotype was obtained in different conditions of selection (in vivo and in vitro for P388/DX and B16VDXR, respectively). In both multidrug-resistant cell lines, an increased expression of P-glycoprotein gene (5 kb transcript detected in Northern blots) was observed and the level of P-glycoprotein mRNA correlated with the degree of resistance. In addition, high molecular weight mRNAs homologous to mdrl gene sequence were consistently detected only in P388/DX cells. Overexpression was associated with a high level of gene amplification only in resistant melanoma cells, whereas it occurred in P388/DX cells with a marginal increase in gene copy number. These results, suggesting that different genetic mechanisms could be responsible for P-glycoprotein overexpression, emphasise the complexity of genetic regulation that may affect tumour cell sensitivity to cytotoxic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis.

Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.

Adult↗
PubMed1997

Production of poly(3-hydroxybutyrate) by fed-batch culture of filamentation-suppressed recombinant Escherichia coli.

Recombinant Escherichia coli XL1-Blue harboring a high-copy-number plasmid containing the Alcaligenes eutrophus polyhydroxyalkanoate synthesis genes could efficiently synthesize poly(3-hydroxybutyrate) (PHB) in a complex medium containing yeast extract and tryptone but not in a defined medium. One of the reasons for the reduced PHB production in a defined medium was thought to be severe filamentation of cells in this medium. By overexpressing an essential cell division protein, FtsZ, in recombinant E. coli producing PHB, filamentation could be suppressed and PHB could be efficiently produced in a defined medium. A high PHB concentration of 149 g/liter, with high productivity of 3.4 g of PHB/liter/h, could be obtained by the pH-stat fed-batch culture of the filamentation-suppressed recombinant E. coli in a defined medium. It was also found that insufficient oxygen supply at a dissolved oxygen concentration (DOC) of 1 to 3% of air saturation during active PHB synthesis phase did not negatively affect PHB production. By growing cells to the concentration of 110 g/liter and then controlling the DOC in the range of 1 to 3% of air saturation, a PHB concentration of 157 g/liter and PHB productivity of 3.2 g of PHB/liter/h were obtained. For the scale-up studies, fed-batch culture was carried out in a 50-liter stirred tank fermentor, in which the DOC decreased to zero when cell concentration reached 50 g/liter. However, a relatively high PHB concentration of 101 g/liter and PHB productivity of 2.8 g of PHB/liter/h could still be obtained, which demonstrated the possibility of industrial production of PHB in a defined medium by employing the filamentation-suppressed recombinant E. coli.

Alcaligenes↗
PubMed1994

Stabilities of quantitative plasma culture for human immunodeficiency virus, RNA, and p24 antigen from samples collected in VACUTAINER CPT and standard VACUTAINER tubes.

We evaluated the stability of human immunodeficiency virus (HIV) load markers from blood samples collected in VACUTAINER CPT or standard VACUTAINER brand tubes using sodium heparin or sodium citrate as anticoagulants. Quantitative plasma culture and p24 antigen concentrations were determined, and HIV RNA levels in plasma were measured by both reverse transcription-PCR-enzyme-linked immunosorbent assay (RT-PCR-ELISA) and branched DNA methods. All tubes were stored at room temperature for analysis at 2, 24, 48, and 72 h after the blood samples were drawn. No difference was seen between tube types with respect to the HIV titer in plasma or the positivity rate for all samples that demonstrated a fall in titer over time. Unbound p24 antigen levels in plasma decreased during the initial 48-h period in both tube types. Immune complex-dissociated p24 antigen levels decreased in CPT tubes but not in standard VACUTAINER tubes. The HIV RNA copy number in plasma measured by RT-PCR-ELISA was stable in most subjects and was significantly higher in CPT tubes than in standard VACUTAINER tubes at 24 and 72 h after the blood samples were drawn. The branched DNA probe assay detected a significant decline in HIV RNA equivalent in plasma over 72 h in both collection tubes, the decline being more dramatic in the standard VACUTAINER tube than the CPT tube. Overall, interday variability suggests that samples collected for a particular assay should be processed at the same time after blood is drawn and that a particular tube type be used throughout a given study.

Anticoagulants↗
PubMed1999

Evolution and clonal traits of Mycobacterium tuberculosis complex in Guinea-Bissau.

Two hundred twenty-nine consecutive isolates of Mycobacterium tuberculosis complex from patients with pulmonary tuberculosis in Guinea-Bissau, which is located in West Africa, were analyzed for clonal origin by biochemical typing and DNA fingerprinting. By using four biochemical tests (resistance to thiophene-2-carboxylic acid hydrazide, niacin production, nitrate reductase test, and pyrazinamidase test), the isolates could be assigned to five different biovars. The characteristics of four strains conformed fully with the biochemical criteria for M. bovis, while those of 85 isolates agreed with the biochemical criteria for M. tuberculosis. The remaining 140 isolates could be allocated into one of three biovars (biovars 2 to 4) representing a spectrum between the classical bovine (biovar 1) and human (biovar 5) tubercle bacilli. By using two genotyping methods, restriction fragment length polymorphism analysis with IS6110 (IS6110 RFLP analysis) and spoligotyping, the isolates could be separated into three groups (groups A to C) of the M. tuberculosis complex. Group A (n = 95), which contained the majority of classical human M. tuberculosis isolates, had large numbers of copies of IS6110 elements (mean number of copies, 9) and a distinctive spoligotyping pattern that lacked spacers 33 to 36. Isolates of the major group, group B (n = 119), had fewer IS6110 copies (mean copy number, 5) and a spoligotyping pattern that lacked spacers 7 to 9 and 39 and mainly comprised isolates of biovars 1 to 4. Group C isolates (n = 15) had one to three IS6110 copies, had a spoligotyping pattern that lacked spacers 29 to 34, and represented biovar 3 to 5 isolates. Four isolates whose biochemical characteristics conformed with those of M. bovis clustered with the group B isolates and had spoligotype patterns that differed from those previously reported for M. bovis, in that they possessed spacers 40 to 43. Interestingly, isolates of group B and, to a certain extent, also isolates of group C showed a high degree of variability in biochemical traits, despite genotypic identity in terms of IS6110 RFLP and spoligotype patterns. We hypothesize that isolates of groups B and C have their evolutionary origin in West Africa, while group A isolates are of European descent.

Adult↗
PubMed2004

Spinal muscular atrophy: molecular genetics and diagnostics.

Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future.

Animals↗