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C C Morton

Publications and source records attributed to C C Morton.

At least 73 records · Page 4Linked to original sources
PubMed1998

ORC5L, a new member of the human origin recognition complex, is deleted in uterine leiomyomas and malignant myeloid diseases.

A new member of the human origin recognition complex (ORC) was cloned and identified as ORC5L. HsORC5p is a 50-kDa protein whose sequence is 38% identical and 62% similar to ORC5p from Drosophila melanogaster. Two alleles of ORC5L were identified, one with and one without an evolutionarily conserved purine nucleotide binding motif. HsORC5p is precipitated from cell extracts with HsORC2p and HsORC4p, indicating that it is part of the putative human ORC. The bulk of HsORC5p is in an insoluble nuclear fraction, whereas the other known human ORC subunits (HsORC1p, HsORC2p, and HsORC4p) are easily extracted in the nuclear-soluble fractions and in S100 (HsORC1p). In addition, we identified an alternatively spliced mRNA from the same locus (HsORC5T). HsORC5Tp also formed a complex with HsORC4p but not with HsORC2p, suggesting it may play a regulatory role in the assembly of different ORC subcomplexes. HsORC5, HsORC5T, and HsORC4 transcripts are abundant in spleen, ovary, and prostate in addition to tissues with high levels of DNA replication like testes and colon mucosa, implicating the human ORC proteins in functions besides DNA replication. Finally, the gene for ORC5L is located at chromosome 7, band q22, in the minimal region deleted in 10% of uterine leiomyomas and in 10-20% of acute myeloid leukemias and myelodysplastic syndromes.

Alternative Splicing↗
PubMed1998

Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects.

Polycystin-1 and polycystin-2 are the products of PKD1 and PKD2, genes that are mutated in most cases of autosomal dominant polycystic kidney disease. Polycystin-2 shares approximately 46% homology with pore-forming domains of a number of cation channels. It has been suggested that polycystin-2 may function as a subunit of an ion channel whose activity is regulated by polycystin-1. Here we report the identification of a human gene, PKDL, which encodes a new member of the polycystin protein family designated polycystin-L. Polycystin-L has 50% amino acid sequence identity and 71% homology to polycystin-2 and has striking sequence and structural resemblance to the pore-forming alpha1 subunits of Ca2+ channels, suggesting that polycystin-L may function as a subunit of an ion channel. The full-length transcript of PKDL is expressed at high levels in fetal tissues, including kidney and liver, and down-regulated in adult tissues. PKDL was assigned to 10q24 by fluorescence in situ hybridization and is linked to D10S603 by radiation hybrid mapping. There is no evidence of linkage to PKDL in six ADPKD families that are unlinked to PKD1 or PKD2. The mouse homologue of PKDL is deleted in Krd mice, a deletion mutant with defects in the kidney and eye. We propose that PKDL is an excellent candidate for as yet unmapped cystic diseases in man and animals.

Amino Acid Sequence↗
PubMed1998

Human ARHGDIG, a GDP-dissociation inhibitor for Rho proteins: genomic structure, sequence, expression analysis, and mapping to chromosome 16p13.3.

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activity of GTPases. We recently reported the identification of a new GDI for the Rho-related GTPases named RhoGDIgamma. This gene is now designated ARHGDIG by HUGO. Here, in a detailed analysis of tissue expression of ARHGDIG, we observe high levels in the entire brain, with regional variations. The mRNA is also present at high levels in kidney and pancreas and at moderate levels in spinal cord, stomach, and pituitary gland. In other tissues examined, the mRNA levels are very low (lung, trachea, small intestine, colon, placenta) or undetectable. RT-PCR analysis of total RNA isolated from exocrine pancreas and islets shows that the gene is expressed in both tissues. We also report the genomic structure of ARHGDIG. The gene spans over 4 kb and is organized into six exons and five introns. The upstream region lacks a canonical TATA box and contains several putative binding sites for ubiquitous and tissue-specific factors active in central nervous system development. Using FISH, we have mapped the gene to chromosome band 16p13.3. This band is rich in deletion mutants of genes involved in several human diseases, notably polycystic kidney disease, alpha-thalassemia, tuberous sclerosis, mental retardation, and cancer. The promoter structure and the chromosomal location of RhoGDIgamma suggest its importance and underscore the need for further investigation into its biology.

Base Sequence↗
PubMed1998

Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19.

The DFNB7/11 locus for autosomal recessive non-syndromic hearing loss (ARNSHL) has been mapped to an approx. 1.5 Mb interval on human chromosome 9q13-q21. We have determined the cDNA sequence and genomic structure of a novel cochlear-expressed gene, ZNF216, that maps to the DFNB7/11 interval. The mouse orthologue of this gene maps to the murine dn (deafness) locus on mouse chromosome 19. The ZNF216 gene is highly conserved between human and mouse, and contains two regions that show homology to the putative zinc linger domains of other proteins. To determine it mutations in ZNF216 might be the cause of hearing loss at the DFNB7/11 locus, we screened the coding region of this gene in DFNB7/11 families by direct sequencing. No potential disease-causing mutations were found. In addition, Northern blot analysis showed no difference in ZNF216 transcript size or abundance between dn and control mice. These data Suggest that the ZNF216 gene is unlikely to be responsible for hearing loss at the DFNB7/11 and dn loci.

Algorithms↗
PubMed1998

Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.

Usher syndrome type IIa (OMIM 276901), an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, maps to the long arm of human chromosome 1q41 between markers AFM268ZD1 and AFM144XF2. Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region. The USH2A gene encodes a protein with a predicted size of 171.5 kilodaltons that has laminin epidermal growth factor and fibronectin type III motifs; these motifs are most commonly observed in proteins comprising components of the basal lamina and extracellular matrixes and in cell adhesion molecules.

Amino Acid Sequence↗
PubMed1998

Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3.

DFNB3, a locus for nonsyndromic sensorineural recessive deafness, maps to a 3-centimorgan interval on human chromosome 17p11.2, a region that shows conserved synteny with mouse shaker-2. A human unconventional myosin gene, MYO15, was identified by combining functional and positional cloning approaches in searching for shaker-2 and DFNB3. MYO15 has at least 50 exons spanning 36 kilobases. Sequence analyses of these exons in affected individuals from three unrelated DFNB3 families revealed two missense mutations and one nonsense mutation that cosegregated with congenital recessive deafness.

Amino Acid Sequence↗
PubMed1998

Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans.

The molecular basis for autosomal dominant progressive nonsyndromic hearing loss in an Israeli Jewish family, Family H, has been determined. Linkage analysis placed this deafness locus, DFNA15, on chromosome 5q31. The human homolog of mouse Pou4f3, a member of the POU-domain family of transcription factors whose targeted inactivation causes profound deafness in mice, was physically mapped to the 25-centimorgan DFNA15-linked region. An 8-base pair deletion in the POU homeodomain of human POU4F3 was identified in Family H. A truncated protein presumably impairs high-affinity binding of this transcription factor in a dominant negative fashion, leading to progressive hearing loss.

Adult↗
PubMed1998

Localization and expression of the human estrogen receptor beta gene in uterine leiomyomata.

Estrogens have an important function in the natural history of uterine leiomyomata. The human estrogen receptor beta gene (ESR2) has been identified recently and mapped to 14q22-24, a region frequently rearranged in uterine leiomyomata and other benign tumors, including pulmonary chondroid hamartomas and endometrial polyps. Using fluorescence in situ hybridization and radiation hybrid mapping, we map ESR2 within 14q23-24.1, to a region approximately 2 Mb centromeric to the t(12;14) breakpoint in uterine leiomyomata, between markers D14S63 and WI-7536. Two YAC clones, 948B6 and 741H4, contain ESR2. Using RT-PCR, we show that ESR2 is expressed in uterine leiomyomata and pulmonary chondroid hamartomas as well as in normal myometrium. Lack of a direct relationship between rearrangement of 14q23-24 and ESR2 expression suggests that ESR2 is not involved with HMGIC or HMGIY in t(12;14) or t(6;14). However, because of its relatively close physical distance from the characteristic site of rearrangements in 14q23-24, a role for ESR2 in the pathobiology of these tumors warrants future consideration.

Chromosome Mapping↗
PubMed1998

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction.

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Amino Acid Sequence↗
PubMed1998

Inner ridge cells may be the main source of tectorial membrane type II collagen: evidence from quantitative mRNA in situ hybridization.

In a previous study we showed that COL2A1 mRNA is expressed in both ectodermally and mesodermally derived structures of second trimester human fetal cochlea, whereas type II collagen is present in mesodermally derived structures and in tectorial and basilar membranes. Because the tectorial membrane is acellular and therefore does not make its own proteins, the source of type II collagen and proteoglycans in this membrane has been of interest. We have attempted to address this issue, at least in part, by performing quantitative cRNA mRNA in situ hybridization on second trimester human fetal cochlear sections using a COL2A1 probe. By counting the number of silver grains cell in the interdental cells, inner sulcus cells and inner ridge Kolliker organ cells and by an analysis of variance of these quantitative data. inner ridge cells were found to have significantly higher levels of COL2A1 mRNA than interdental and inner sulcus cells (p < 0.0001). On the basis of significantly higher COL2A1 mRNA levels in inner ridge cells and their higher numbers than interdental and inner sulcus cells we postulate that type II collagen for human fetal tectorial membrane is derived mostly from inner ridge Kolliker organ cells. The lower COL2A1 mRNA in interdental cells appears to provide type II collagen for the spiral limbus and the tectorial membrane. The inner sulcus cells, hair cells. Deiter's and Hensen's cells also appear to contribute lesser amounts of type II collagen to the tectorial membrane. In analogy to these findings it is possible that other tectorial membrane proteins, including proteoglycans and other collagens, are also largely derived from these cells during human fetal development.

Cochlea↗
PubMed1998

Cytogenetic abnormalities in uterine myomas are associated with myoma size.

Uterine leiomyomata (myomas) are associated with a variety of characteristic cytogenetic abnormalities. The significance of these chromosomal aberrations in the pathobiology of myomas remains to be determined. The present study investigated the relationship between myoma cytogenetic abnormalities and size. A total of 114 myoma specimens were obtained from 92 patients undergoing myomectomy or hysterectomy. The maximum diameter of each myoma was measured and a portion of each myoma obtained for cytogenetic analysis. Karyotypes were analysed and categorized as normal, abnormal (non-mosaic) or mosaic. Cytogenetic analyses revealed 73 (64%) normal, 20 (18%) abnormal (non-mosaic), and 21 (18%) mosaic karyotypes. Mean myoma diameter was 6.5+/-0.44 cm with a range of 0.4-27 cm. Differences between the mean myoma diameter of specimens with normal versus abnormal karyotypes was determined by the Kruskal-Wallis test. The mean myoma diameter among specimens with abnormal (non-mosaic) karyotypes was significantly greater than myomas with normal karyotypes (10.2+/-5.9 versus 5.9+/-4.2 cm; P < 0.001). The proportion of abnormal (non-mosaic) karyotypes in myomas >6.5 cm was compared to myomas <6.5 cm by chi2-analysis; myomas >6.5 cm demonstrated a significantly higher proportion of abnormal (non-mosaic) karyotypes when compared to myomas <6.5 cm (75 versus 34%; P < 0.02). In summary, a significant relationship exists between clonal cytogenetic abnormalities and myoma size, suggesting that chromosomal abnormalities associated with individual myomas enhance myoma growth.

Adult↗
PubMed1997

Mapping and characterization of a novel cochlear gene in human and in mouse: a positional candidate gene for a deafness disorder, DFNA9.

Previously we identified a partial human cDNA for a novel cochlear transcript, hCoch-5B2 (HGMW-approved symbol D14S564E), using subtractive hybridization techniques. Herein we report isolation and characterization of both human and mouse (D12H14S564E) cDNAs for Coch-5B2. Full-length Coch5B2 deduced amino acid sequences reveal a very high degree of conservation in the coding region (89% nucleotide and 94% amino acid identity and a potential signal peptide and two regions of extensive homology to the collagen-binding type A domains of von Willebrand factor, also present in other secreted proteins, including extracellular matrix components. High levels of hCoch-5B2 expression are seen only in human fetal inner ear structures, cochlea, and vestibule, among a large panel of human fetal and adult tissues. Coch-5B2 expression in the mouse is more widespread than in the human, with message detected in mouse adult spleen, cerebrum, cerebellum/medulla, and thymus. In both species very low level expression is detected in total eye. More specifically, mouse retina shows a higher level of mCoch-5B2 message than sclera and choroid. We have mapped hCoch-5B2 to human 14q11.2-q13 by somatic cell hybrid analysis and FISH and, more precisely, using radiation hybrids to a region of markers linked to DFNA9, a nonsyndromic autosomal dominant sensorineural hearing loss with vestibular defects. Furthermore, we detect hCoch-5B2 on three overlapping YACs, two of which also contain one of the markers linked to DFNA9. mCoch-5B2 was genetically mapped in the mouse to chromosome 12, in a region of homologous synteny with human 14q11.2-q13, which contains the asp1 (audiogenic seizure prone) locus in the mouse.

Amino Acid Sequence↗
PubMed1997

An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1).

We constructed and screened a human fetal cochlear cDNA library to identify genes involved in hearing and deafness. From this library we isolated a cDNA corresponding to the highly conserved ancient gene antiquitin (ATQ1). The plant homolog of ATQ1 is thought to be involved in regulating turgor pressure, a function that also would be essential for cells of the mammalian cochlea. Northern blots of 13 human fetal tissues show antiquitin to be highly expressed in cochlea, ovary, eye, heart, and kidney. Using RT-PCR of rat cochlear hair cell-specific cDNA libraries, we detect antiquitin expression in outer hair cells, but not in inner or vestibular type 1 hair cells, suggesting that antiquitin is not expressed ubiquitously in the cochlea. Human ATQ1 was mapped to human chromosome region 5q31 using fluorescence in situ hybridization, and mouse ATQ1 was mapped to mouse chromosome 18 by single-strand conformation polymorphism mapping of interspecific backcross progeny DNAs. Four human antiquitin-like sequences, possibly pseudogenes, were also identified and mapped.

Adaptor Proteins, Signal Transducing↗
PubMed1997

The del(7q) subgroup in uterine leiomyomata: genetic and biologic characteristics. Further evidence for the secondary nature of cytogenetic abnormalities in the pathobiology of uterine leiomyomata.

Rearrangement of 7q represents one of the major cytogenetic subgroups in uterine leiomyomata, the most common tumors arising in females. Herein we report cytogenetic analysis on a series of 22 cases of uterine leiomyomata with 7q abnormalities, and describe observations regarding tumor size and maintenance of the tumor cells in culture. We discuss the frequent finding of mosaic tumors containing both cells with the 7q rearrangement and karyotypically normal cells. Clonality studies of three mosaic cases reveal nonrandom X chromosome inactivation substantiating prior findings suggesting the secondary nature of chromosome aberrations in these tumors. Genes mapped in 7q22 and those identified in the pathobiology of other uterine leiomyomata subgroups are discussed in addition to a perspective on the role of the 7q22 leiomyomata gene.

Chromosome Deletion↗
PubMed1997

Identification, localization, and expression of two novel human genes similar to deoxyribonuclease I.

Two novel cDNAs, DNAS1L2 and DNAS1L3, are predicted to encode proteins of 299 and 305 amino acids with 56 and 46% residue identity (71 and 63% similarity), respectively, to deoxyribonuclease I (DNase I). DNAS1L2 is located on a 16p13.3 cosmid, while DNAS1L3 maps to 3p14.3-p21.1 by fluorescence in situ hybridization and by PCR analysis of a radiation hybrid panel. Northern analysis revealed DNAS1L3 expression nearly exclusively in liver, while DNAS1L2 expression was detected in brain by RT-PCR. The previously defined DNL1L or DNAS1L1 is expressed highest in heart and skeletal muscle, while DNase I is expressed in the pancreas, parotid gland, and kidney. Thus, to date, four DNase I-like genes that show different tissue expression patterns are known. A comparison of DNAS1L1, DNAS1L2, and DNAS1L3 with the well-characterized DNase I suggests that the DNAS1L proteins are unlikely to be glycosylated or bind actin; however, catalytic and calcium- and DNA-binding residues are conserved, and potentially cleavable signal peptides are present among all these proteins. This analysis also identifies regions of high conservation among these proteins with no currently assigned function.

Amino Acid Sequence↗