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J R Lupski

Publications and source records attributed to J R Lupski.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cloning, genomic structure, and expression of mouse ring finger protein gene Znf179.

ZNF179, a RING finger protein encoding gene, has been mapped within the critical deletion region for Smith-Magenis syndrome (SMS), a disorder characterized by mental retardation and multiple congenital anomalies associated with del(17)(p11.2). Here we report the cloning of Znf179, the mouse homologue of ZNF179, and characterization of its gene structure. The 3028-bp cDNA has a 1.9-kb open reading frame that contains a RING finger domain at its N-terminus and an alanine-rich and glycine-rich domain at its C-terminus. Znf179 genomic sequence includes 15 introns and spans about 10 kb on mouse chromosome 11, which maintains conserved synteny with human 17p. Northern analysis indicates that Znf179 is predominantly expressed in brain and testis. Although contained within the SMS common deletion interval, FISH experiments show that ZNF179 is not deleted in two SMS patients with smaller deletions.

Abnormalities, Multiple↗
PubMed1998

A novel locus for Leber congenital amaurosis on chromosome 14q24.

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous autosomal recessive retinal dystrophy and the most common genetic cause of congenital visual impairment. We used a DNA pooling strategy comparing the genotypes of affected to unaffected control pools in a genome-wide search for identity-by-descent on a consanguineous Saudi Arabian LCA family. A shift to homozygosity was observed in the affected DNA pool compared with the control pool at linked markers D14S606 and D14S610. Genotyping of individual DNA samples from the entire pedigree for marker D14S74, closely linked to these loci, and several flanking markers confirmed linkage with a ZMAX=13.29 at theta=0.0. These data assign a third locus (LCA3) for LCA to chromosome 14q24. This locus and the previously identified loci are excluded for other Saudi Arabian pedigrees, both confirming that this clinical disorder is genetically heterogeneous and that additional LCA genes remain to be identified.

Chromosomes, Human, Pair 14↗
PubMed1998

Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits.

Molecular medicine began with Pauling's seminal work, which recognized sickle-cell anemia as a molecular disease, and with Ingram's demonstration of a specific chemical difference between the hemoglobins of normal and sickled human red blood cells. During the four decades that followed, investigations have focused on the gene--how mutations specifically alter DNA and how these changes affect the structure and expression of encoded proteins. Recently, however, the advances of the human genome project and the completion of total genome sequences for yeast and many bacterial species, have enabled investigators to view genetic information in the context of the entire genome. As a result, we recognize that the mechanisms for some genetic diseases are best understood at a genomic level. The evolution of the mammalian genome has resulted in the duplication of genes, gene segments and repeat gene clusters. This genome architecture provides substrates for homologous recombination between nonsyntenic regions of chromosomes. Such events can result in DNA rearrangements that cause disease.

Chromosome Aberrations↗
PubMed1998

Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.

The early growth response 2 gene (EGR2) is part of a multigene family encoding Cys2His2 type zinc-finger proteins and may play a role in the regulation of cellular proliferation. Egr2, (also known as Krox20) is the mouse orthologue of human EGR2 and was first identified as an immediate-early response gene, encoding a protein that binds DNA in a sequence-specific manner and acts as a transcription factor. Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage. We hypothesized that Egr2 may be a transcription factor affecting late myelin genes and that human myelinopathies of the PNS may result from mutations in EGR2. In support of this hypothesis, we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1).

Adolescent↗
PubMed1998

Cell cycle arrest in Era GTPase mutants: a potential growth rate-regulated checkpoint in Escherichia coli.

Era is a low-molecular-weight GTPase essential for Escherichia coli viability. The gene encoding Era is found in the rnc operon, and the synthesis of both RNase III and Era increases with growth rate. Mutants that are partially defective in Era GTPase activity or that are reduced in the synthesis of wild-type Era become arrested in the cell cycle at the predivisional two-cell stage. The partially defective Era GTPase mutation (era1) suppresses several temperature-sensitive lethal alleles that affect chromosome replication and chromosome partitioning but not cell division. Our results suggest that Era plays an important role in cell cycle progression at a specific point in the cycle, after chromosome partitioning but before cytokinesis. Possible functions for Era in cell cycle progression and the initiation of cell division are discussed.

Amino Acid Sequence↗
PubMed1998

Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia.

The autosomal recessive disorder primary congenital glaucoma (PCG) is caused by unknown developmental defect(s) of the trabecular meshwork and anterior chamber angle of the eye. Homozygosity mapping with a DNA pooling strategy in three large consanguineous Saudi PCG families identified the GLC3A locus on chromosome 2p21 in a region tightly linked to PCG in another population. Formal linkage analysis in 25 Saudi PCG families confirmed both significant linkage to polymorphic markers in this region and incomplete penetrance, but it showed no evidence of genetic heterogeneity. For these 25 families, the maximum combined two-point LOD score was 15.76 at a recombination fraction of .021, with the polymorphic marker D2S177. Both haplotype analysis and homozygosity mapping in these families localized GLC3A to a 5-cM critical interval delineated by markers D2S2186 and D2S1356. Sequence analysis of the coding exons for cytochrome P4501B1 (CYP1B1) in these 25 families revealed three distinctive mutations that segregate with the phenotype in 24 families. Additional clinical and molecular data on some mildly affected relatives showed variable expressivity of PCG in this population. These results should stimulate a study of the genetic and environmental events that modify the effects of CYP1B1 mutations in ocular development. Furthermore, the small number of PCG mutations identified in this Saudi population makes both neonatal and population screening attractive public health measures.

Adult↗
PubMed1998

Genetic mapping refines DFNB3 to 17p11.2, suggests multiple alleles of DFNB3, and supports homology to the mouse model shaker-2.

The nonsyndromic congenital recessive deafness gene, DFNB3, first identified in Bengkala, Bali, was mapped to a approximately 12-cM interval on chromosome 17. New short tandem repeats (STRs) and additional DNA samples were used to identify recombinants that constrain the DFNB3 interval to less, similar6 cM on 17p11.2. Affected individuals from Bengkala and affected members of a family with hereditary deafness who were from Bila, a village neighboring Bengkala, were homozygous for the same alleles for six adjacent STRs in the DFNB3 region and were heterozygous for other distal markers, thus limiting DFNB3 to an approximately 3-cM interval. Nonsyndromic deafness segregating in two unrelated consanguineous Indian families, M21 and I-1924, were also linked to the DFNB3 region. Haplotype analysis indicates that the DFNB3 mutations in the three pedigrees most likely arose independently and suggests that DFNB3 makes a significant contribution to hereditary deafness worldwide. On the basis of conserved synteny, mouse deafness mutations shaker-2 (sh2) and sh2J are proposed as models of DFNB3. Genetic mapping has refined sh2 to a 0.6-cM interval of chromosome 11. Three homologous genes map within the sh2 and DFNB3 intervals, suggesting that sh2 is the homologue of DFNB3.

Alleles↗
PubMed1998

Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients.

The HNPP (hereditary neuropathy with liability to pressure palsies) deletion and CMT1A (Charcot-Marie-Tooth disease type 1A) duplication are the reciprocal products of homologous recombination events between misaligned flanking CMT1A-REP repeats on chromosome 17p11. 2-p12. A 1.7-kb hotspot for homologous recombination was previously identified wherein the relative risk of an exchange event is 50 times higher than in the surrounding 98.7% identical sequence shared by the CMT1A-REPs. To refine the region of exchange further, we designed a PCR strategy to amplify the recombinant CMT1A-REP from HNPP patients as well as the proximal and distal CMT1A-REPs from control individuals. By comparing the sequences across recombinant CMT1A-REPs to that of the proximal and distal CMT1A-REPs, the exchange was mapped to a 557-bp region within the previously identified 1.7-kb hotspot in 21 of 23 unrelated HNPP deletion patients. Two patients had recombined sequences suggesting an exchange event closer to the mariner-like element previously identified near the hotspot. Five individuals also had interspersed patches of proximal or distal repeat specific DNA sequence indicating potential gene conversion during the exchange of genetic material. Our studies provide a direct observation of human meiotic recombination products. These results are consistent with the hypothesis that minimum efficient processing segments, which have been characterized in Escherichia coli, yeast, and cultured mammalian cells, may be required for efficient homologous meiotic recombination in humans.

Charcot-Marie-Tooth Disease↗
PubMed1998

SERE, a widely dispersed bacterial repetitive DNA element.

The presence of a Salmonella serotype Enteritidis repeat element (SERE) located within the upstream regulatory region of the sefABCD operon encoding fimbrial proteins is reported. DNA dot-blot hybridisation analyses and computerised searches of genetic databases indicate that SERE is well conserved and widely distributed throughout the bacterial and archaeal kingdoms. A SERE-based polymerase chain reaction (SERE-PCR) assay was developed to fingerprint 54 isolates of Enteritidis representing nine distinct phage types and 54 isolates of other Salmonella serotypes. SERE-PCR identified five distinct fingerprint profiles among the 54 Enteritidis isolates; no correlation between phage types and SERE-PCR fingerprint patterns was noticed. SERE-PCR was reproducible, rapid and easy to perform. The results of this investigation suggest that the limited heterogeneity of SERE-PCR fingerprint patterns can be utilised to develop serotype- and serogroup-specific fingerprint patterns for isolates of Enteritidis.

Animals↗
PubMed1998

Charcot-Marie-Tooth phenotype produced by a duplicated PMP22 gene as part of a 17p trisomy-translocation to the X chromosome.

The Charcot-Marie-Tooth disease type 1A (CMT1A) phenotype is most often associated with a 1.5 megabase (mb), tandem duplication of chromosome 17 band p12 (17p12). The prevailing hypothesis is that the demyelinating neuropathy results from a dosage effect of the peripheral myelin protein gene PMP22 which is included within this duplication. We present a patient with clinical and electrophysiological features of CMT1A in whom an extra PMP22 gene resulted from a rare unbalanced translocation of 17p to the X chromosome. This finding further supports the hypothesis of gene dosage as the basis for CMT1A. Moreover, this case highlights the importance of fluorescence in situ hybridization (FISH) as an alternative molecular technique in the diagnosis of CMT1A.

Adult↗
PubMed1997

Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of severe central visual impairment among the elderly and is associated both with environmental factors such as smoking and with genetic factors. Here, 167 unrelated AMD patients were screened for alterations in ABCR, a gene that encodes a retinal rod photoreceptor protein and is defective in Stargardt disease, a common hereditary form of macular dystrophy. Thirteen different AMD-associated alterations, both deletions and amino acid substitutions, were found in one allele of ABCR in 26 patients (16%). Identification of ABCR alterations will permit presymptomatic testing of high-risk individuals and may lead to earlier diagnosis of AMD and to new strategies for prevention and therapy.

ATP-Binding Cassette Transporters↗
PubMed1997

Severe clinical phenotype due to an interstitial deletion of the short arm of chromosome 1: a brief review.

We report on a newborn girl with malformed ears, bilateral cleft lip and cleft palate, complex congenital heart disease, absent left thumb, and rib abnormalities. Cytogenetic analysis demonstrated a de novo interstitial deletion of the short arm of chromosome 1 [46,XX,del(1)(p21p22.3)]. Reports of interstitial deletions on the short arm of chromosome 1 are rare. However, when comparing this patient's phenotype to others with deletions of 1p, we found that the current case was much more severely affected than previously reported cases.

Abnormalities, Multiple↗
PubMed1997

Genomic structure, evolution, and expression of human FLII, a gelsolin and leucine-rich-repeat family member: overlap with LLGL.

The Drosophila melanogaster flightless-I gene is involved in cellularization processes in early embryogenesis and in the structural organization of indirect flight muscle. The encoded protein contains a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat protein-protein interaction domain. The homologous human FLII gene encodes a 1269-residue protein with 58% amino acid sequence identity and is deleted in Smith-Magenis syndrome. We have cloned the FLII gene and determined its nucleotide sequence (14.1 kb). FLII has 29 introns, compared with 13 in Caenorhabditis elegans and 3 in D. melanogaster. The positions of several introns are conserved in FLII-related genes and in the domains and subdomains of the gelsolin-like regions giving indications of gelsolin gene family evolution. In keeping with its function in indirect flight muscle in Drosophila, the human FLII gene was most highly expressed in muscle. The FLII gene lies adjacent to LLGL, the human homologue of the D. melanogaster tumor suppressor gene lethal(2) giant larvae. The 3' end of the FLII transcript overlaps the 3' end of the LLGL transcript, and the corresponding mouse genes Fliih and Llglh also overlap. The overlap region contains poly(A) signals for both genes and is strongly conserved between human and mouse.

Animals↗
PubMed1997

Genomic structure and expression of the human heme A:farnesyltransferase (COX10) gene.

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem DNA duplication in chromosome 17p11.2-p12, while hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. The 1.5-Mb CMT1A monomer unit duplicated in CMT1A and deleted in HNPP is flanked by two 24-kb direct repeats termed the CMT1A-REPs. Recently, sequence analysis of the CMT1A-REPs revealed that they contain an internal exon of the COX10 gene. To characterize COX10, encoding human heme A:farnesyltransferase, the genomic region was isolated and the gene structure and expression profile were determined. COX10 spans approximately 135 kb and consists of seven exons. Exons I-V are telomeric to the 1.5-Mb CMT1A monomer unit, whereas exon VII is located within this 1.5-Mb region. Exon VI is contained within the distal CMT1A-REP. All splice sites conform to the GT/AG rule. Analysis of the putative promoter region of the COX10 gene indicates that it lacks conventional TATA and CAAT boxes, but it does have several potential transcription factor-binding sites. This gene is expressed in multiple tissues with highest expression observed in the heart, skeletal muscle, and testis.

Alkyl and Aryl Transferases↗
PubMed1997

Charcot-Marie-Tooth disease: a gene-dosage effect.

A broad spectrum of inherited neuropathy has been traced to three myelin genes, yet in the two most common disorders, there is no mutated gene. Instead, a gene has an extra or missing copy, as part of a 1.5-megabase DNA duplication or deletion. Eventually, duplications may emerge as a large fraction of all mutations. The discoveries have implications even for acquired disorders--including carpal tunnel syndrome.

Carpal Tunnel Syndrome↗
PubMed1997

Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory.

Charcot-Marie-Tooth (CMT) disease type 1A is an inherited peripheral neuropathy characterized by slowly progressive distal muscle wasting and weakness, decreased nerve conduction velocities, and genetic linkage to 17p12. Most (> 98%) CMT1A cases are caused by a DNA duplication of a 1.5-Mb region in 17p12 containing the PMP22 gene. The reciprocal product of the CMT1A duplication is a 1.5-Mb deletion which causes hereditary neuropathy with liability to pressure palsies (HNPP). The most informative current diagnostic testing requires pulsed-field gel electrophoresis to detect DNA rearrangement-specific junction fragments. We investigated the use of interphase FISH for the detection of duplications and deletions for these disorders in the clinical molecular cytogenetics laboratory. Established cell lines or blood specimens from 23 individuals with known molecular diagnoses and 10 controls were obtained and scored using a two-color FISH assay. At least 70% of CMT1A cells displayed three signals consistent with duplications. Using this minimum expected percentile to make a CMT1A duplication diagnosis, all patients with CMT1A showed a range of 71-92% of cells displaying at least three signals. Of the HNPP cases, 88% of cells displayed only one hybridization signal, consistent with deletions. The PMP22 locus from normal control individuals displayed a duplication pattern in approximately 9% of cells, interpreted as replication of this locus. The percentage of cells showing replication was significantly lower than in those cells displaying true duplications. We conclude that FISH can be reliably used to diagnose CMT1A and HNPP in the clinical cytogenetics laboratory and to readily distinguish the DNA rearrangements associated with these disorders from individuals without duplication or deletion of the PMP22 locus.

Cell Line↗
PubMed1997

Isolation of novel genes from the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12.

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem DNA duplication in chromosome 17p11.2-p12, while hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. The 1.5-Mb CMT1A monomer unit duplicated in CMT1A and deleted in HNPP is flanked by low-copy repeats termed CMT1A-REPs. Both diseases appear to be caused by an altered copy number of the peripheral myelin protein 22 gene (PMP22), which lies within the critical region. To identify additional genes rapidly, we used a cosmid contig of this region and reciprocal probing of arrayed chromosome 17-specific cosmid and cDNA libraries. Three cDNA clones were identified within the CMT1A duplication/HNPP deletion region and one just proximal to the critical region. The cDNA for human heme A:farnesyltransferase (COX10) mapped 10 kb centromeric to the distal CMT1A-REP. The other two cDNA clones from within the critical interval mapped to cosmid 126D1 at the mfd41 (D17S261) DNA marker, and their conceptual translation showed homology to 60S ribosomal protein L9 (RPL9) and chromosomal protein RMSA-1 (RMSA-1). A gene that is homologous to human peroxisome proliferator activated receptor alpha (hPPARA) was identified near the proximal CMT1A-REP.

Alkyl and Aryl Transferases↗