The fibroblast growth factors in multiple myeloma.
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Cell Line, Tumor↗
Biomedical subjects
W R Wilcox
Publications and source records attributed to W R Wilcox.
A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases.
Osteogenesis imperfecta (OI) is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. We identified a mutation in the carboxyl-terminal propeptide coding region of one COL1A1 allele in an infant who died with an OI phenotype that differed from the usual lethal form and had regions of increased bone density. The newborn female had dysmorphic facial features, including loss of mandibular angle. Bilateral upper and lower limb contractures were present with multiple fractures in the long bones and ribs. The long bones were not compressed and their ends were radiographically dense. She died after a few hours and histopathological studies identified extramedullary haematopoiesis in the liver, little lamellar bone formation, decreased osteoclasts, abnormally thickened bony trabeculae with retained cartilage in long bones, and diminished marrow spaces similar to those seen in dense bone diseases such as osteopetrosis and pycnodysostosis. The child was heterozygous for a COL1A1 4321G-->T transversion in exon 52 that changed a conserved aspartic acid to tyrosine (D1441Y). Abnormal proalpha1(I) chains were slow to assemble into dimers and trimers, and abnormal molecules were retained intracellularly for an extended period. The secreted type I procollagen molecules synthesised by cultured dermal fibroblasts were overmodified along the full length but had normal thermal stability. These findings suggest that the unusual phenotype reflected both a diminished amount of secreted type I procollagen and the presence of a population of stable and overmodified molecules that might support increased mineralisation or interfere with degradation of bone.
Amino Acid Substitution↗
Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.
BACKGROUND: Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS: We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS: In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.
Adolescent↗
A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda.
Spondyloepiphyseal dysplasia tarda (SEDL) is a genetically heterogeneous disorder characterized by mild-to-moderate short stature and early-onset osteoarthritis. Both autosomal and X-linked forms have been described. Elsewhere, we have reported the identification of the gene for the X-linked recessive form, which maps to Xp22.2. We now report characterization of an exon-skipping mutation (IVS3+5G-->A at the intron 3 splice-donor site) in two unrelated families with SEDL. Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. The mutation was not detected in 120 control X chromosomes. Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER). RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae. The latter homologue, p20, has a putative role in vesicular transport from ER to Golgi complex. These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.
Adult↗
"Baby rattle" pelvis dysplasia.
We report an apparently previously undescribed lethal skeletal dysplasia, clinically resembling achondrogenesis, but with distinct radiologic and chondro-osseous morphologic features. These comprise bifid distal ends of the long bones of the limbs, absent vertebral body ossification, a unique "baby rattle" pelvic configuration with tall and broad ilia, absent endochondral ossification, regions of mesenchymal cells within the resting cartilage, and abnormal mesenchymal ossification.
Achondroplasia↗
Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3.
A unique type of craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis.
Acanthosis Nigricans↗
Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development.
Dyssegmental dysplasia, Silverman-Handmaker type (DDSH), is a lethal autosomal recessive form of dwarfism with characteristic anisospondylic micromelia. The remarkable similarities in the radiographic, clinical, and chondroosseous morphology of DDSH patients to those of perlecan-null mice led to the identification of mutations in the perlecan gene (HSPG2) of DDSH. Perlecan, a large heparan sulfate proteoglycan, is expressed in various tissues and is a component of all basement membrane extracellular matrices. A chondrodysplasia phenotype caused by the loss of perlecan was unexpected, because cartilage does not have basement membranes. Insertion and splicing mutations in HSPG2 of DDSH were found that were predicted to create a premature termination codon. Immunostaining and biochemical analysis revealed that the mutant perlecan molecules were unstable and not secreted into the extracellular matrix. These results indicate that DDSH is caused by functional null mutations of HSPG2 and that perlecan is essential for cartilage development. Published 2002 Wiley-Liss, Inc.
Cartilage↗
Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene.
Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage, and is implicated in cell growth and differentiation. Mice lacking the perlecan gene (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development.
Animals↗
Uruguay facio-cardio-musculo-skeletal syndrome: a novel X-linked recessive disorder.
We report on three male patients from a single family with a brachyturricephaly, "pugilistic" facial appearance, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. Three other males in the family, now deceased from cardiac disease, appear to have had the same disorder. The mother of the propositus has milder signs of the syndrome. All affected males are related through the maternal line. These cases represent an apparently previously undescribed X-linked recessive syndrome.
Abnormalities, Multiple↗
Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chondro-osseous morphology.
Oto-palato-digital syndrome type II (OPD II) is a lethal X-linked skeletal dysplasia with pleiotropic manifestations. The basic defect is not known. There has been only one detailed report of the chondro-osseous abnormalities in this condition describing abnormal periosteal ossification in a single case [1990: Am J Med Genet 36:226-231]. We report on three cases of OPD II emphasizing the chondro-osseous morphology. Although endochondral ossification was normal, periosteal ossification was defective with islands of cortical bone aplasia and hyperplasia of the periosteum. The trabecular bone was also extremely poorly formed and markedly hypercellular. Both membranous ossification and bone remodeling appear to be defective in OPD II and should account for part of the observed phenotype. The biglycan gene maps to Xq28 and is involved in bone formation, but was excluded as a candidate by direct sequencing of cDNA in one case.
Abnormalities, Multiple↗
Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia.
Previous linkage analysis (Briggs, M.D., Choi, H.-C., Warman, M.L. et al., 1994. Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM 2) to a region of chromosome 1 containing a type IX collagen gene. Am. J. Hum. Genet. 55, 678-684) in a large English family with multiple epiphyseal dysplasia established the EDM2 locus, a region of chromosome 1 containing the COL9A2 collagen gene. We now report that affected members of this family are heterozygous for a single base transversion (T-->G) at the sixth position of the intron 3 splice donor of COL9A2. The mutation leads to skipping of exon 3 during splicing, and results in a 36-nucleotide deletion in COL9A2 transcripts derived from the mutant allele. Skipping of exon 3 predicts an in-frame deletion of 12 amino acid residues within the COL3 domain of the alpha2(IX) chain. This is the fifth instance of an exon 3 deletion within the COL3 region of collagen IX heterotrimers causing the MED phenotype, as yet the only type IX collagen defect identified in this disorder. Electron microscopy (EM) of chondrocytes obtained from articular cartilage of one affected individual in the family demonstrated normal appearing rough endoplasmic reticulum (RER). In addition, the articular cartilage matrix did not show any gross abnormalities in the quantity or caliber of collagen fibrils.
Alleles↗
Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes.
Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.
Asphyxia↗
Small deletions in the type II collagen triple helix produce kniest dysplasia.
Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.
Base Sequence↗
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.
We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.
Acanthosis Nigricans↗
Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations.
The platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of short-limb dwarfing conditions. The most common form of PLSD is thanatophoric dysplasia (TD), which has been divided into two types (TD1 and TD2). Three other types of PLSD, or TD variants (San Diego, Torrance, and Luton), have been distinguished from TD. The most notable difference between TD and the variants is the presence of large rough endoplasmic reticulum (rER) inclusion bodies within chondrocytes of the variants. We examined 22 cases of TD variants for the presence of missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. All 17 cases of the San Diego type (PLSD-SD) were heterozygous for the same FGFR3 mutations found in TD1. No mutations were identified in the Torrance and Luton types. Large inclusion bodies were found in all 14 cases of PLSD-SD. Similar inclusion bodies were present in two of 72 TD1 cases, but not in 39 controls. The material retained within the rER stained only with antibody to the FGFR3 protein. The radiographic and morphologic differences between TD and PLSD-SD may be a consequence of other genetic factors, perhaps in the processing of mutant FGFR3 molecules within the rER. The presence of rER inclusion bodies cannot reliably discriminate between closely related skeletal dysplasias.
Chondrocytes↗
Lethal osteosclerotic skeletal dysplasia with intracellular inclusion bodies.
We report an apparently previously undescribed form of lethal osteosclerotic skeletal dysplasia in a 30-week male fetus with micromelic shortness of the limbs. Radiographic findings at necropsy included increased density in all bones, most marked in the skull, mandible, and pubis. The ribs were very short, abnormally modeled, and wide anteriorly. The vertebrae were posteriorly hypoplastic and wedged, particularly in the cervical and lumbar regions. The femora and tibiae were short with wide distal metaphyses, undermodeled diaphyses, and coxa vara. The humeri, radii, and ulnae were also short and undermodeled with proximal and distal flare. Chondro-osseous morphology showed short chondrocyte columns, extension of hypertrophic cells into the metaphysis, and overgrowth of perichondral bone. In the resting cartilage there were large chondrocytes containing a homogeneous material staining pink with von Kossa trichrome, gray with toluidine blue, and black with silver methenamine. The cortical bone was lacking and the trabecular bone was hypercellular, thick, and coarse. Ultrastructurally, the resting zone chondrocytes were large and round with condensed chromatin and dilated loops of rough endoplasmic reticulum. The radiographic and histopathologic findings in this case are unique and differ from those seen in other reported lethal osteosclerotic skeletal dysplasias.
Abnormalities, Multiple↗
Clinical spectrum of fibroblast growth factor receptor mutations.
During the last few years, it has been demonstrated that some syndromic craniosynostosis and short-limb dwarfism syndromes, a heterogeneous group comprising of 11 distinct clinical entities, are caused by mutations in one of three fibroblast growth factor receptor genes (FGFR1, FGFR2, and FGFR3). The present review list all mutations described to date in these three genes and the phenotypes associated with them. In addition, the tentative phenotype-genotype correlation is discussed, including the most suggested causative mechanisms for these conditions.
Bone Diseases, Developmental↗
Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome.
X-linked dominant Conradi-Hünermann syndrome (CDPX2; MIM 302960) is one of a group of disorders with aberrant punctate calcification in cartilage, or chondrodysplasia punctata (CDP). This is most prominent around the vertebral column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis and atrophoderma. The phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. CDPX2 is presumed lethal in males, although a few affected males have been reported. We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples from seven female probands with CDPX2 (ref. 4). This pattern of accumulated cholesterol intermediates suggested a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-delta8-isomerase (EBP) has been identified and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands. We confirmed the functional significance of two missense alleles by expressing them in a sterol-delta8-isomerase-deficient yeast strain. Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and suggest a role for sterols in bone development.
Adolescent↗