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Biomedical subjects

B D Gelb

Publications and source records attributed to B D Gelb.

At least 37 records · Page 2Linked to original sources
PubMed1999

Sanjad-Sakati and autosomal recessive Kenny-Caffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement.

The Sanjad-Sakati syndrome (SSS; MIM241410), an autosomal recessive trait characterized by congenital hypoparathyroidism, growth and mental retardation, seizures, and a characteristic physiognomy, was recently linked to chromosome area 1q42-q43. SSS resembles the autosomal recessive form of Kenny-Caffey syndrome (KCS; MIM244460), with similar manifestations but lacking osteosclerosis. Since KCS was recently linked to the region 1q42-q43, the possibility that this disorder is allelic with SSS was considered. Eight Sanjad-Sakati families from Saudi Arabia were genotyped with polymorphic short tandem repeat markers from the SSS/KCS critical region. A maximum multipoint LOD score of 14.32 was obtained at marker D1S2649, confirming linkage of SSS to the same region as autosomal recessive KCS. Haplotype analysis refined the critical region to 2.6 cM and identified a rare haplotype present in all the SSS disease alleles, indicative of a common founder. In addition to the assignment of the Saudi SSS and Kuwaiti KCS syndromes to overlapping genetic intervals, comparison of the haplotypes unexpectedly demonstrated that the diseases shared an identical haplotype. This finding, combined with the clinical similarity between the two syndromes, suggests that the two conditions are not only allelic but are also caused by the same ancestral mutation.

Abnormalities, Multiple↗
PubMed1999

Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21.

BACKGROUND: Patent ductus arteriosus (PDA) is a relatively common form of congenital heart disease. Although polygenic inheritance has been implicated, no specific gene defects causing PDA have been identified to date. Thus, a positional cloning strategy was undertaken to determine the gene responsible for the Char syndrome, an autosomal dominant disorder characterized by PDA, facial dysmorphism, and hand anomalies. METHODS AND RESULTS: A genome scan was performed with 46 members of 2 unrelated families in which the disease was fully penetrant but the phenotype differed. Significant linkage was achieved with several polymorphic DNA markers mapping to chromosome 6p12-p21 (maximal 2-point LOD score of 8.39 with D6S1638 at theta=0.00). Haplotype analysis identified recombinant events that defined the Char syndrome locus with high probability to a 3. 1-cM region between D6S459/D6S1632/D6S1541 and D6S1024. CONCLUSIONS: A familial syndrome in which PDA is a common feature was mapped to a narrow region of chromosome 6p12-p21. Additional analysis with other families and polymorphic markers as well as evaluation of potential candidate genes should lead to the identification of the Char syndrome gene, which will provide insights into cardiogenesis as well as limb and craniofacial development.

Chromosome Mapping↗
PubMed1999

Localization of the thiamine-responsive megaloblastic anemia syndrome locus to a 1.4-cM region of 1q23.

Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive syndrome characterized by megaloblastic anemia, deafness, and diabetes mellitus. A genome scan previously established linkage of this disorder to 1q23 and haplotype analysis defined a 16-cM critical region. Molecular genetic analyses of four unrelated multiplex Iranian families inheriting TRMA confirmed linkage to the same region and identified recombinant chromosomes which permitted refinement of the critical region to a narrow 1.4-cM interval. The haplotypes of the families differed, consistent with at least two independent mutational events. This refinement of the TRMA locus to less than 10% of that previously published should markedly facilitate the identification and evaluation of positional candidate and novel genes which may cause this disorder.

Anemia, Megaloblastic↗
PubMed1999

Isolation, characterization, and mapping of four novel polymorphic markers and an H3.3B pseudogene to chromosome 9p21-22.

Alterations in chromosomal region 9p21-22 are among the most frequently encountered cytogenetic changes present in a number of human malignancies. In addition, the causative genes of a number of hereditary cancers have been genetically mapped to this region. We describe the isolation and precise localization of four novel polymorphic markers and a previously identified marker, D9S1846, from this region. Moreover, we have identified a retroposon-rich area within this oncogenic region containing a processed H3.3B pseudogene flanked by an L1 sequence and an Alu element. Together, these finely mapped and ordered reagents should prove useful for genetic mapping, sequencing, and loss of heterozygosity studies of the 9p21-22 region.

Base Sequence↗
PubMed1999

Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome.

Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus. Treatment with pharmacologic doses of thiamine ameliorates the megaloblastic anaemia and diabetes mellitus. A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cultured skin fibroblasts from TRMA patients. The gene causing TRMA was assigned to 1q23.2-q23.3 by linkage analysis. Here we report the cloning of a new gene, SLC19A2, identified from high-through-put genomic sequences due to homology with SLC19A1, encoding reduced folate carrier 1 (refs 8-10). We cloned the entire coding region by screening a human fetal brain cDNA library. SLC19A2 encodes a protein (of 497 aa) predicted to have 12 transmembrane domains. We identified 2 frameshift mutations in exon 2. a 1-bp insertion and a 2-bp deletion, among four Iranian families with TRMA. The sequence homology and predicted structure of SLC19A2, as well as its role in TRMA, suggest that its gene product is a thiamine carrier, the first to be identified in complex eukaryotes.

Amino Acid Sequence↗
PubMed1999

Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22.

Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal dominant bone dysplasia/cancer syndrome of unknown etiology. This rare hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, pathological fractures, and eventual painful debilitation. Notably, 35% of individuals with DMS develop MFH, a highly malignant bone sarcoma. A genome scan for the DMS-MFH gene locus in three unrelated families with DMS-MFH linked the syndrome to a region of approximately 3 cM on chromosome 9p21-22, with a maximal two-point LOD score of 5.49 (marker D9S171 at recombination fraction [theta].05). Interestingly, this region had previously been shown to be the site of chromosomal abnormalities in several other malignancies and contains a number of genes whose protein products are involved in growth regulation. Identification of this rare familial sarcoma-causing gene would be expected to simultaneously define the cause of the more common nonfamilial, or sporadic, form of MFH-a tumor that constitutes approximately 6% of all bone cancers and is the most frequently occurring adult soft-tissue sarcoma.

Bone Diseases, Developmental↗
PubMed1999

CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1. To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families. The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth. Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies.

Animals↗
PubMed1999

Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis.

Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia. To investigate the nature of molecular lesions causing this disease, mutations in the cathepsin K gene from eight families were determined, identifying seven novel mutations (K52X, G79E, Q190X, Y212C, A277E, A277V, and R312G). Expression of the first pro region missense mutation in a cysteine protease, G79E, in Pichia pastoris resulted in an unstable precursor protein, consistent with misfolding of the proenzyme. Expression of five mature region missense defects revealed that G146R, A277E, A277V, and R312G precursors were unstable, and no mature proteins or protease activity were detected. The Y212C precursor was activated to its mature form in a manner similar to that of the wild-type cathepsin K. The mature Y212C enzyme retained its dipeptide substrate specificity and gelatinolytic activity, but it had markedly decreased activity toward type I collagen and a cathepsin K-specific tripeptide substrate, indicating that it was unable to bind collagen triple helix. These studies demonstrated the molecular heterogeneity of mutations causing pycnodysostosis, indicated that pro region conformation directs proper folding of the proenzyme, and suggested that the cathepsin K active site contains a critical collagen-binding domain.

Cathepsin K↗
PubMed1999

Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation.

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.

Acid Phosphatase↗
PubMed1998

The autosomal recessive Kenny-Caffey syndrome locus maps to chromosome 1q42-q43.

Kenny-Caffey syndrome (KCS) is an osteosclerotic bone dysplasia with associated hypocalcemia and ocular abnormalities. Both autosomal dominant (MIM127000) and autosomal recessive (MIM244460) inheritance patterns have been described. Using eight consanguineous Kuwaiti kindreds, a genome-wide search for linkage to the gene causing the autosomal recessive form of KCS was performed with polymorphic short tandem repeat markers. Significant linkage to a locus situated at chromosome 1q42 --> q43 with a maximal two-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at markers D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in another consanguineous KCS kindred, was not documented in these families.

Abnormalities, Multiple↗
PubMed1998

Usefulness of tacrolimus versus cyclosporine after pediatric heart transplantation.

This study compared the early clinical course of 9 pediatric heart transplantation recipients treated with cyclosporine A-based immunosuppression with 10 similarly aged recipients treated with tacrolimus-based therapy. One-year follow-up after transplantation revealed that tacrolimus-treated children had similar left ventricular function, experienced fewer episodes of severe rejection, were more rapidly weaned from corticosteroids, and had relatively few side effects from immunosuppression compared with cyclosporine A-treated children.

Adolescent↗
PubMed1998

Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis.

Molecular analysis of a patient affected by the autosomal recessive skeletal dysplasia, pycnodysostosis (cathepsin K deficiency; MIM 265800), revealed homozygosity for a novel missense mutation (A277V). Since the A277V mutation was carried by the patient's father but not by his mother, who had two normal cathepsin K alleles, paternal uniparental disomy was suspected. Karyotyping of the patient and of both parents was normal, and high-resolution cytogenetic analyses of chromosome 1, to which cathepsin K is mapped, revealed no abnormalities. Evaluation of polymorphic DNA markers spanning chromosome 1 demonstrated that the patient had inherited two paternal chromosome 1 homologues, whereas alleles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping near the chromosome 1 centromere, but he was heteroallelic for markers near both telomeres, establishing that the paternal uniparental disomy with partial isodisomy was caused by a meiosis II nondisjunction event. Phenotypically, the patient had normal birth height and weight, had normal psychomotor development at age 7 years, and had only the usual features of pycnodysostosis. This patient represents the first case of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.

Adult↗
PubMed1998

Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome.

Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.

Adult↗
PubMed1998

The effects of HLA mismatching and immunosuppressive therapy on early rejection outcome in pediatric heart transplant recipients.

BACKGROUND: Although HLA-DR antigen mismatching between heart transplant recipients and donors has been associated with increased early allograft rejection in adult patients treated with cyclosporine, little information exists in the pediatric age group. In this study we examined retrospectively the effects of HLA mismatching and immunosuppression choice, cyclosporine versus tacrolimus on early rejection outcome in pediatric heart transplant recipients. METHODS: Between 1992 and 1997, 38 patients (ages 10 days to 18 years) underwent 40 heart transplantations. All recipients were typed prospectively and donors retrospectively by use of serologic microcytotoxicity testing for HLA-A and HLA-B antigens and by a polymerase chain reaction technique for HLA-DR antigens. All heart transplant recipients received induction immunosuppression with methylprednisolone and maintenance prednisone, and 38 received OKT3. The first 25 heart transplant recipients received cyclosporine and azathioprine, and the last 15 were given tacrolimus. Clinical courses, HLA mismatching, and biopsy results for the first year after heart transplantation were reviewed and compared between treatment groups. RESULTS: Mean age, donor/recipient weight ratios, and biopsies/patient were similar between treatment groups. Five deaths occurred among cyclosporine-treated patients and none among tacrolimus-treated patients during the study period. HLA mismatching was similar between groups, with 94% of patients having 1 or 2 HLA-A mismatches and 96% having 1 or 2 HLA-B and -DR mismatches. Both International Society for Heart and Lung Transplantation grade 2 and grade 3 or 4 rejections were significantly increased in biopsies from cyclosporine-treated patients (P < .05). Significantly increased grade 3 or 4 rejection was present in patients treated with cyclosporine who had two DR mismatches versus those with one DR mismatch (3.0+/-1.6 vs 1.4+/-0.8; P < .05); no statistical significance between patients treated with tacrolimus with 1 vs 2 DR mismatches was noted. Patients treated with tacrolimus who had 2 DR mismatches had fewer grade 3 or 4 rejection episodes/patient than either patients treated with cyclosporine who had one DR mismatch (0.6+/-0.4 vs 1.4+/-0.8, P = .03) or those treated with cyclosporine who had two DR mismatches (0.6+/-0.4 vs 3.0+/-1.6, P = .01). Grade 3 or 4 rejection episodes/patient were not affected by HLA-A or B mismatching, and grade 2 rejection was not affected by mismatching at any of the loci. CONCLUSION: Although mismatching of HLA-A and -B antigens did not affect frequency of early cellular rejection, the presence of 2 HLA-DR loci mismatches increased the risk of high-grade rejection in pediatric heart transplant recipients treated with cyclosporine. The potent effects of tacrolimus-based immunosuppression mitigated the impact of HLA-DR mismatching, because patients treated with tacrolimus who had 2 DR mismatches had less rejection than even patients treated with cyclosporine who had one DR mismatch and seemed to be at no greater risk for rejection than patients treated with tacrolimus who had 1 DR mismatch.

Adolescent↗
PubMed1997

Clinical implications and possible association of malposition of the branch pulmonary arteries with DiGeorge syndrome and microdeletion of chromosomal region 22q11.

We describe a series of 10 patients with malposition of the branch pulmonary arteries (4 patients with crossing [crossed pulmonary arteries] and 6 patients without crossing), 2 of whom had a short main pulmonary artery segment that resulted in iatrogenic right pulmonary artery stenosis after pulmonary artery band placement. DiGeorge syndrome was seen in 5 patients and 4 had microscopic deletion of chromosomal region 22q11.

Adolescent↗
PubMed1997

Structure and chromosomal assignment of the human cathepsin K gene.

Cathepsin K is a recently identified lysosomal cysteine proteinase that is the major protease responsible for bone resorption and remodeling. Mutations in this gene cause the sclerosing osteochondrodysplasia pycnodysostosis. To assess its evolutionary relatedness to other cysteine proteases and to facilitate mutation identification in patients with pycnodysostosis, a genomic clone, 74e16, containing the cathepsin K gene was isolated from a human PAC library, and the cathepsin K genomic structure was determined. The cathepsin K gene contained eight exons and spanned approximately 9 kb. The transcription initiation site, determined by primer extension analysis, was 169 nucleotides upstream from the translation initiation site. The 5'-flanking region lacked a TATA box but contained two AP1 sites. Comparison of genomic and cDNA sequences suggested that this flanking sequence may be the major promoter in osteoclasts and macrophages. Cathepsin K was mapped to chromosome 1q21 by fluorescence in situ hybridization and found to reside within 150 kb of an evolutionarily related cysteine protease, cathepsin S. These findings expand our understanding of the papain family lysosomal cysteine proteases and should facilitate mutation analysis in pycnodysostosis.

Base Sequence↗