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PubMed1994

The exon-intron structure and chromosomal localization of the mouse macrophage mannose receptor gene Mrc1: identification of a Ricin-like domain at the N-terminus of the receptor.

The macrophage mannose receptor is a transmembrane protein that is expressed on the surface of mature macrophages. The ectodomain of the receptor contains multiple domains, eight of which belong to the calcium-dependent C-type lectin family. The mannose receptor binds to carbohydrate polymers that have a high content of mannose. This property allows this protein to function as a phagocytic receptor that participates in first-line host defense against invading microorganisms. In this paper we describe the intron-exon structure of the mouse macrophage mannose receptor gene which was found to span at least 70 kilobases. We also report the localization of this gene, termed Mrc1, to mouse Chromosome 2. Like its human counterpart, Mrc1 contains 30 exons and 29 introns. A protein module that resembles a subdomain of the B chain of the plant lectin Ricin has been found within the N-terminal cysteine-rich domain of the mannose receptor.

3T3 Cells↗
PubMed2005

Evidence for telomeric fusions as a mechanism for recurring structural aberrations of chromosome 11 in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a benign but often aggressive tumor with a tendency toward local recurrence. Telomeric associations (tas) or telomeric fusions are common cytogenetic findings that have been implicated in the initiation of chromosome instability and tumorigenesis. We performed cytogenetic studies on 5 cases of GCTB to further characterize chromosome aberrations in these tumors. Four of the 5 cases showed abnormal karyotypes with clonal telomeric fusions involving chromosome 11. In 3 cases, the telomeric fusions of 11pter were apparently the precursor lesions to the progression of sub-clones with structural chromosome aberrations of 11p. Two tumors demonstrated a similar pattern of progression resulting in whole arm losses of 11p, including sub-clones with both whole-arm unbalanced translocations and whole-arm deletions. A third tumor with clonal tas of 11pter showed 2 additional subclones, one with ring chromosome 11 and the other with an extra copy of 1q. To our knowledge, the 2 cases with del(11)(p11) represent the first report of a recurring structural chromosome aberration in GCTB. These findings support the concept that telomeric instability is responsible for a large degree of intratumor heterogeneity and serves as a precursor lesion to subsequent clonal structural aberrations of chromosome 11 in GCTB.

Adolescent↗
PubMed1999

Structure and chromosomal locations of mouse steroid receptor coactivator gene family.

The newly recognized steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) belong to a homologous gene family and are important transcriptional mediators for nuclear receptors. Through fluorescence in situ hybridization, we have mapped the mouse SRC-1, SRC-2, and SRC-3 genes to chromosomal locations 12A2-A3, 1A3-A5, and 2H2-H4, respectively. By screening a mouse genomic DNA library, performing long-range polymerase chain reaction and sequencing, we have cloned and characterized the mouse SRC-3 gene. The SRC-3 gene contains 19 exons and spans more than 38 kilobases (kb). Intron sizes are variable. Intron 1 (13.5 kb) and intron 15 (4.6 kb) contribute to almost half the total length of the gene. Among 20 exons identified, exon 10 is the largest (869 bp) and encodes the receptor interaction domain. The start and stop codons for translation are in exon 2 and 20, respectively. The relationship between SRC-3 gene structure and its functional protein domains suggests that many functional domains or subdomains are encoded by individual exons. The correlation between gene structure and alternative splice variants is also discussed. In summary, we have defined the structure of mouse SRC-3 gene and found that the genes in the SRC family are located in different mouse chromosomes. This information is important for developing valuable animal models harboring multiple disruptions of the SRC gene family to study their biological functions.

Animals↗
PubMed2004

Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines.

Chromosomal aberrations are common in cancers. However, the search for chromosomal aberrations leading to development of specific solid tumors has been severely hindered because the majority of solid tumors have complex chromosomal aberrations that differ within the same tumor types. A similar phenomenon exists in immortalized cell lines. The underlying mechanisms driving these diverse aberrations are largely unknown. Telomeres play crucial roles in protecting the integrity of eucaryotic chromosomes and maintaining genomic stability of human cells. Telomere lengths on individual chromosomes in normal human somatic cells are heterogeneous and undergo progressive shortening with aging process. In this study, for the first time, a molecular cytogenetic method using sequential telomere quantitative fluorescence in situ hybridization and spectral karyotyping on the same human metaphases was applied successfully to examine the dynamic profiles of individual telomere shortening and their relationship to chromosome aberrations in multiple human cell lines undergoing immortalization. Human ovarian surface epithelial cells and esophageal epithelial cells were immortalized by the expression of HPV16 E6 and E7, which drive cells to proliferate by inactivating p53 and Rb genes. In these cell lines, we consistently detected large-scale differences in telomere signal intensities not only among nonhomologous chromosome arms but also between some homologous chromosome arms. The cell lines derived from different donors had different profiles of critically short telomeres (lacking telomere signals). Strikingly, the different profiles of chromosomal structural aberrations in multiple immortalized cell lines were highly significantly associated with the distinct distributions of critically short telomeres in whole-genome. Since cellular immortalization is one of the hallmarks of cancer, our findings suggest that distinct profiles of critically short telomeres in different human individuals might play an essential role in determining the complex and individual-specific chromosomal structural aberrations in human solid tumors.

Cell Line, Transformed↗
PubMed2000

Gene encoding the mouse sulphamidase: cDNA cloning, structure, and chromosomal mapping.

Sulphamidase is an exoglycosidase involved in the degradation of heparan sulfate. Lack of sulphamidase activity leads to the lysosomal storage disorder Mucopolysaccharidosis type IIIA (Sanfilippo type A OMIM No. 252900). At present there are no naturally occurring small animal models of this disease that could be of fundamental importance to study the pathophysiology of the disease and to try therapeutic strategies. Cloning of the mouse gene is an important step to create a mouse model for this common mucopolysaccharidosis. We have isolated and sequenced the gene encoding mouse sulphamidase. Comparison of the deduced amino acid sequences of human and mouse sulphamidase showed 88% identity and 93% similarity. The exon-intron structure of the gene has been determined with the mouse 10-kb gene divided in 8 exons. The mouse sulphamidase gene (Sgsh) was mapped to the distal end of Chromosome (Chr) 11, in a region that is homologous with a segment of human Chr 17 containing the orthologous human gene.

Amino Acid Sequence↗
PubMed1995

Prenatal cytogenetic abnormalities: correlations of structural rearrangements and ultrasonographically detected fetal anomalies.

OBJECTIVE: Our purpose was to determine the distribution of karyotypic abnormalities detected at prenatal diagnosis, fetal anomalies, and ability for fluorescent in situ hybridization detection. STUDY DESIGN: Our cytogenetic database from January 1988 to April 1994 was categorized according to type and potential detection by current standard fluorescent in situ hybridization probes. Fetal anomalies and cytogenetic aberrations were compared. RESULTS: A total of 664 cases of abnormal fetal karyotypes were identified from 12,454 prenatal cytogenetic cases (7529 amniocenteses and 4925 chorionic villus sampling) and were classified as autosomal aneuploidy (331), sex aneuploidy (103), polyploidy (38), marker aneuploidy (19) and structural rearrangements (173). Standard fluorescent in situ hybridization probes would have missed 31% of the abnormal cases: 90 aneuploidy, 14 de novo marker aneuploidy, and 65 de novo structural aberrant cases. The 134 cases of structural chromosomal rearrangements with complete ultrasonographic records were further classified as polymorphism (42), familial (43), or de novo (49). Frequency of fetal anomaly detection by ultrasonography in de novo cases (22/49) was higher than other rearrangements (chi 2 7.4, p = 0.006). CONCLUSION: The contribution of unusual aneuploidies (16%) and structural chromosomal rearrangements (26%) in prenatal diagnostic practice is significant. Fetal anomalies were detected by ultrasonography in 45% of the de novo rearrangement cases. Fluorescent in situ hybridization would miss 31% of the abnormal cases.

Aneuploidy↗
PubMed1997

Chromosomal abnormalities in cutaneous T-cell lymphoma and in its premalignant conditions as detected by G-banding and interphase cytogenetic methods.

The etiology of cutaneous T-cell lymphomas (CTCL) is unknown. We studied the pattern of chromosomal abnormalities with G-banding and interphase in situ hybridization methods in blood mononuclear cells in 17 patients representing the different phases of CTCL or the premalignant condition, parapsoriasis en plaque, and in 10 control persons. We used biotinylated centromere-specific probes with fluorescent detection (FISH) for chromosomes 1, 11, 8, and 17 and similar, enzymatically detectable, digoxigenin-labeled probes for chromosomes 1, 6, 12, 17, and 18. In G-banding, all patients showed numerical and structural chromosome aberrations. Numerical aberrations of chromosomes 6, 13, 15, and 17, marker chromosomes, and structural aberrations of chromosomes 3, 9, and 13 were increased in mycosis fungoides (MF) compared with healthy controls. In four of five patients the detection of a chromosomal clone preceded relapse or progression of the disease. In FISH of interphase cells, the cells abnormal for chromosomes 8 or 11, and for all four chromosomes collectively, were increased in MF and in Sezary Syndrome (SS). FISH and G-banding methods agreed statistically significantly for the detection of monosomy. Also, digoxigenin-labeled probes hybridized to interphases or mitoses detected aberrations corresponding to those observed with G-banding. Thus, chromosomally abnormal cells can be found in the peripheral blood of both parapsoriasis en plaque and CTCL patients. They can be detected with interphase cytogenetical methods, which obviates the need for dividing cells, often difficult to accomplish in CTCL.

Adult↗
PubMed1998

Human chondroitin 6-sulfotransferase: cloning, gene structure, and chromosomal localization.

Chondroitin 6-sulfotransferase (C6ST) is the key enzyme in the biosynthesis of chondroitin 6-sulfate, a glycosaminoglycan implicated in chondrogenesis, neoplasia, atherosclerosis, and other processes. C6ST catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to carbon 6 of the N-acetylgalactosamine residues of chondroitin. Based on the previously published avian sequence, we searched the database of expressed sequence tags (dbEST) and obtained partial-length cDNAs that we completed by 5'-RACE using human chondrosarcoma and endothelial-cell RNA as template. Stable transfection of our full-length expression construct into CHO-K1 cells resulted in marked increases in C6ST and keratan sulfate sulfotransferase (KSST) enzymatic activities in cell homogenates. The predicted 411 amino acid sequence of human C6ST contains an N-terminal hydrophobic domain consistent with membrane insertion, four potential sites for N-linked glycosylation, several consensus sequences for protein phosphorylation, and one RGD sequence. The human and chick C6ST cDNA share 51% nucleotide identity, 40% amino acyl identity, and 75% amino acyl conservation. The human C6ST gene structure has been elucidated and exhibits an intron-less coding region, and the gene has been mapped to human chromosome 11 by radiation hybrid panel mapping.

Acetylgalactosamine↗
PubMed1998

Characterization of the breakpoints in a t(8;13)(p11;q12) translocation from a patient with myeloproliferative disease using fluorescence in situ hybridization.

We used fluorescence in situ hybridization to characterize the molecular position of the breakpoints in a t(8;13)(p11;q12) reciprocal translocation from a patient with an atypical myeloproliferative disorder. This structural chromosome abnormality is characteristic of this specific disease and occurs often as the only chromosome abnormality in the malignant cells. Yeast artificial chromosome (YAC) analysis has demonstrated that the 8p11 breakpoint lies within a region defined by YAC 959A4 and that the 13q12 breakpoint is spanned by YAC 769F9. Identifying the position of the breakpoints in this rearrangement provides the means to search for candidate genes rearranged by this highly specific structural chromosome abnormality.

Adult↗
PubMed1989

Azoospermic male with a balanced Y-autosome translocation.

Structural chromosomal aberrations, such as translocations or inversions, may cause spermatogenic failure. We report a rare chromosomal anomaly 46,X,t(Y;3)(q12;p21) in an azoospermic male with normal phenotype. Twenty-two cases of a balanced Y-autosome translocation have been reported in the literature and the majority of them have been detected among azoospermic males at male infertility clinics. This structural chromosomal anomaly brings spermatogenic arrest at the primary or secondary spermatocyte.

Adult↗
PubMed1992

Genomic structure and chromosomal mapping of the murine CD40 gene.

The B cell-associated surface molecule, CD40, is likely to play a central role in the expansion of Ag-stimulated B cells, and their interaction with activated Th cells. In our study we have isolated genomic clones of murine CD40 from a mouse liver genomic DNA library. Comparison with the murine CD40 cDNA sequence revealed the presence of nine exons that together contain the entire murine CD40 coding region, and span approximately 16.3 kb of genomic DNA. The intron/exon structure of the CD40 gene resembles that of the low affinity nerve growth factor receptor gene, a close homolog of both human and murine CD40. In both cases the functional domains of the receptor molecules are separated onto different exons throughout the genes. Southern blot analysis demonstrated that murine CD40 is a single copy gene that maps in the distal region of mouse chromosome 2.

Amino Acid Sequence↗
PubMed2002

Acute lymphoblastic leukaemia: diagnosis and classification.

Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease with distinct biological and prognostic groupings. Diagnosis relies on traditional cytomorphological and immunohistochemical evaluation of the leukaemic blasts. Subsequently, cytogenetic analysis identifies clonal numeric and/or structural chromosomal abnormalities that may be present, thus confirming the subtype classification and providing important prognostic information for treatment planning. The major chromosomal abnormalities in ALL are t(9;22)(q34;q11), t(12;21)(p13;q22), t(4;11)(q21;q23), t(1;19)(q23;p13), 8q24 translocations and hyperdiploidy. Generally, hyperdiploidy, occurring most frequently in paediatric cases, is associated with a good prognosis, while hypodiploidy confers a poor prognosis. Among structural chromosomal abnormalities, the t(9;22)(q34;q11) resulting in the BCR/ABL fusion protein, and rearrangements of the MLL gene, confer a poor prognosis in both children and adults, while t(12;21)(p13;q22), resulting in the TEL/AML1 fusion protein, and del (12p) confer a good prognosis. More recently, additional diagnostic and prognostic information has been gained from fluorescence in situ hybridization (FISH) and DNA microarray techniques.

Cell Lineage↗
PubMed1998

Genomic structure and chromosomal localization of the human GDNFR-alpha gene.

GDNFR-alpha is a glycosyl-phosphotidylinositol-linked receptor for glial cell line-derived neurotrophic factor (GDNF). GDNF binds to GDNFR-alpha and this complex, in turn, is believed to interact with the RET receptor tyrosine kinase to effect downstream signalling. GDNFR-alpha belongs to a novel gene family without strong homology to known genes. Thus, little information has been available to help predict genomic structure or location of this gene. In this study, the genomic organization of human GDNFR-alpha was delineated through a combination of PAC clone characterization, long distance PCR and sequence analyses. Exon-intron boundaries were defined by comparing the size and sequence of the genomic PCR products to those predicted by the cDNA sequence. The human GDNFR-alpha gene comprises 9 exons. GDNFR-alpha PAC clones were used for FISH analysis to map this gene to 10q26.

Base Sequence↗
PubMed1997

Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA).

Manic-depressive illness is a serious psychiatric disorder that in many, but far from all, patients can be treated with lithium. The main causes for discontinuation of lithium therapy are unpleasant or serious side effects and lack of response. The reason for the striking variation in clinical efficacy of lithium treatment among bipolar patients is not known. The enzyme myo-inositol monophosphatase (IMPase) has been postulated as a target for the mood-stabilizing effects of lithium, but variation in the coding region of the human IMPA gene encoding IMPase activity has not been observed in manic-depressive patients (Steen et al., Pharmacogenetics, 1996, 6, 113-116). It is nevertheless conceivable that polymorphisms or mutations in the noncoding regions of this gene could influence the lithium response in psychiatric patients. As a first step in investigating this possibility, we here report the genomic structure of the human IMPA gene. The gene is composed of at least nine exons and covers more than 20 kb of sequence on chromosome 8q21.13-q21.3. In the 3'-untranslated part of the gene, we observed a polymorphism (a G to A transition) and also two short sequences similar to the inositol/cholin-responsive element consensus. Finally, we postulate that two additional IMPA-like transcripts originate from the human genome, one from a position close to IMPA itself on chromosome 8 and the other from chromosome 18p. Our data may contribute to the identification of genetic factors involved in the pathogenesis and determination of treatment response in manic-depressive illness.

Amino Acid Sequence↗
PubMed1998

Control of meiotic recombination in Schizosaccharomyces pombe.

Homologous recombination occurs at high frequency during meiosis and is essential for the proper segregation of chromosomes and the generation of genetic diversity. Meiotic recombination is controlled in numerous ways. In the fission yeast Schizosaccharomyces pombe nutritional starvation induces meiosis and high-level expression of many genes, including numerous recombination (rec) genes, whose products are required for recombination. Accompanying the two meiotic divisions are profound changes in nuclear and chromosomal structure and movement, which may play an important role in meiotic recombination. Although recombination occurs throughout the genome, it occurs at high frequency in some intervals (hotspots) and at low frequency in others (coldspots). The well-characterized hotspot M26 is activated by the Mts1/Mts2 protein; this site and its binding proteins interact with the local chromosomal structure to enhance recombination. A coldspot between the silent mating-type loci is repressed by identified proteins, which may also alter local chromatin. We discuss in detail the rec genes and the possible functions of their products, some but not all of which share homology with other identified proteins. Although some of the rec gene products are required for recombination throughout the genome, others demonstrate regional specificity and are required in certain genomic regions but not in others. Throughout the review contrasts are made with meiotic recombination in the more thoroughly studied budding yeast Saccharomyces cerevisiae.

Cell Nucleus↗
PubMed1997

Genomic structure and chromosomal localization of the gene encoding translin, a recombination hotspot binding protein.

Human Translin is a novel DNA end binding protein that specifically recognizes consensus sequences at the breakpoint junctions in chromosomal translocations, mostly involving immunoglobulin (Ig)/T-cell receptor gene segments, in human lymphoid neoplasms. We have recently cloned a full-length human Translin cDNA using peptide sequence information obtained from the purified protein. From comparisons of the amino acid sequences in humans and other vertebrates, we conclude that Translin has been highly conserved during evolution, especially at the leucine zipper motif and the basic region, which is thought to be the DNA binding domain. Analysis of the human and mouse Translin genes revealed that they have identical genomic structures consisting of six exons, five introns, and a GC-rich upstream region. In situ hybridization and physical mapping of somatic cell hybrids allowed localization of the gene to human chromosome 2q21.1.

Amino Acid Sequence↗
PubMed2002

cDNA cloning, genomic structure and chromosomal mapping of the mouse glucuronyltransferase-S involved in the biosynthesis of the HNK-1 carbohydrate epitope.

The HNK-1 carbohydrate epitope is expressed on a series of cell adhesion molecules and some glycolipids in the nervous system. Two glucuronyltransferases (GlcAT-P and GlcAT-S) are involved in the biosynthesis of the HNK-1 carbohydrate epitope. In this study, we isolated cDNA and genomic clones encoding the mouse glucuronyltransferase-S involved in the biosynthesis of the HNK-1 carbohydrate epitope and determined the structural organization of the gene. The deduced amino acid sequence of mouse GlcAT-S consists of 324 amino acids and has a type II membrane topology. The predicted amino acid sequence of mouse GlcAT-S is 98.1% identical to that of rat GlcAT-S. Northern blot analysis revealed that the mouse GlcAT-S transcript is specifically expressed in the nervous system. Moreover, the mouse GlcAT-S gene is composed of four exons spanning over more than 25 kilobase pairs. Southern blot analysis and chromosomal mapping indicated that the mouse GlcAT-S gene is a single copy gene and it was mapped to the A4-B region of mouse chromosome 1.

5' Flanking Region↗
PubMed2000

cDNA cloning, expression pattern, genomic structure and chromosomal location of RAB6KIFL, a human kinesin-like gene.

Kinesin-like proteins are microtubule-associated motors that play important roles in intracellular transport and cell division. We report here the characterization of a new human kinesin-like protein, Rabkinesin6 (RAB6KIFL). The composite cDNA sequence is 2957bp, and encodes a protein of 890 amino acids with a predicted molecular weight of 100kDa. It has high homology (93% similarity) with the mouse kinesin-like protein, Rab6kifl, indicating that it is the human homologue of the mouse gene. RAB6KIFL has all of the structural characteristics required to function as a microtubule-associated motor. Unlike the mouse gene which is ubiquitously expressed, RAB6KIFL expression appears to be tissue specific. It is widely expressed in fetal tissues, abundantly expressed in adult thymus, bone marrow and testis, and is expressed at low levels in heart, placenta and spleen. The RAB6KIFL gene is mapped to human chromosome 5, band q31, spans approximately 8.5kb of genomic DNA, and contains 19 exons. RAB6KIFL maps within the smallest commonly deleted segment in myeloid leukemias characterized by a deletion of 5q; however, we detected no mutations of RAB6KIFL in malignant myeloid disorders with loss of 5q. The description of this human kinesin-like protein may provide a better understanding of the diversity of this large family of proteins.

Acute Disease↗