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Andrea Superti-Furga

Publications and source records attributed to Andrea Superti-Furga.

At least 37 records · Page 2Linked to original sources
PubMed2005

A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias including, in order of decreasing severity, achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia. The gene encodes a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate, which is needed for proteoglycan sulfation. To provide new insights in the pathogenetic mechanisms leading to skeletal and connective tissue dysplasia and to obtain an in vivo model for therapeutic approaches to DTD, we generated a Dtdst knock-in mouse with a partial loss of function of the sulfate transporter. In addition, the intronic neomycine cassette in the mutant allele contributed to the hypomorphic phenotype by inducing abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth. The similarity with human DTD makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorders.

Animals↗
PubMed2005

Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.

Animals↗
PubMed2005

Metaphyseal enchondrodysplasia with 2-hydroxy-glutaric aciduria: observation of a third case and further delineation.

In the course of evaluating a 17 months old boy with waddling gait and swollen joints, we found generalized, severe ossification defects in the metaphyses of his long bones. The differential diagnosis included nutritional or genetic rickets, metaphyseal dysplasia, and enchondrodysplasia. Calcium, phosphate and alkaline phosphatase were normal, while targeted analysis of urinary organic acids repeatedly revealed excretion of 2-hydroxy-glutaric acid. Thus, this child appears to have an unusual combination of findings described in just two other patients so far, a girl and a boy, and called 'spondyloenchondrodysplasia with D-2-hydroxy-glutaric aciduria'. These three cases are similar in terms of severe metaphyseal lesions, mild vertebral involvement, and presence of 2-hydroxy-glutaric acid in the urine. We consider this a radiographically and biochemically distinct entity, for which we suggest the name of 'metaphyseal enchondrodysplasia with 2-hydroxy-glutaric aciduria'.

Glutarates↗
PubMed2004

Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) cause a variety of craniosynostosis syndromes. The mutational spectrum tends to be narrow with the majority of mutations occurring in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside of this hotspot are uncommon and the few identified mutations have demonstrated wide clinical variability, making it difficult to establish a clear-cut genotype-phenotype correlation. To better delineate the clinical picture associated with these unusual mutations, we describe a severely affected patient with Pfeiffer syndrome and a missense mutation in the tyrosine kinase (TK) domain of FGFR2.

Acrocephalosyndactylia↗
PubMed2004

Mucolipidosis II presenting as severe neonatal hyperparathyroidism.

UNLABELLED: Mucolipidosis II (ML II or I-cell disease ) (OMIM 252500) is an autosomal recessive lysosomal enzyme targeting disorder that usually presents between 6 and 12 months of age with a clinical phenotype resembling Hurler syndrome and a radiological picture of dysostosis multiplex. When ML II is severe enough to be detected in the newborn period, the radiological changes have been described as similar to hyperparathyroidism or rickets. The biological basis of these findings has not been explored and few biochemical measurements have been recorded. We describe three unrelated infants with ML II who had radiological features of intrauterine hyperparathyroidism and biochemical findings consistent with severe secondary neonatal hyperparathyroidism (marked elevation of serum parathyroid hormone and alkaline phosphatase levels). The vitamin D metabolites were not substantially different from normal and repeatedly normal calcium concentrations excluded vitamin D deficiency rickets and neonatal severe hyperparathyroidism secondary to calcium-sensing receptor gene mutations (OMIM 239200). The pathogenesis of severe hyperparathyroidism in the fetus and newborn with ML II is unexplained. We hypothesize that the enzyme targeting defect of ML II interferes with transplacental calcium transport leading to a calcium starved fetus and activation of the parathyroid response to maintain extracellular calcium concentrations within the normal range. CONCLUSION: Newborns with mucolipidosis II can present with radiological and biochemical signs of hyperparathyroidism. Awareness of this phenomenon may help in avoiding diagnostic pitfalls and establishing a proper diagnosis and therapy.

Bone Diseases, Metabolic↗
PubMed2004

Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2.

Bruck syndrome (BS) is a recessively-inherited phenotypic disorder featuring the unusual combination of skeletal changes resembling osteogenesis imperfecta (OI) with congenital contractures of the large joints. Clinical heterogeneity is apparent in cases reported thus far. While the genes coding for collagen 1 chains are unaffected in BS, there is biochemical evidence for a defect in the hydroxylation of lysine residues in collagen 1 telopeptides. One BS locus has been mapped at 17p12, but more recently, two mutations in the lysyl hydroxylase 2 gene (PLOD2, 3q23-q24) have been identified in BS, showing genetic heterogeneity. The proportion of BS cases linked to 17p22 (BS type 1) or caused by mutations in PLOD2 (BS type 2) is still uncertain, and phenotypic correlations are lacking. We report on a boy who had congenital contractures with pterygia at birth and severe OI-like osteopenia and multiple fractures. His urine contained high amounts of hydroxyproline but low amounts of collagen crosslinks degradation products; and he was shown to be homozygous for a novel mutation leading to an Arg598His substitution in PLOD2. The mutation is adjacent to the two mutations previously reported (Gly601Val and Thr608Ile), suggesting a functionally important hotspot in PLOD2. The combination of pterygia with bone fragility, as illustrated by this case, is difficult to explain; it suggests that telopeptide lysyl hydroxylation must be involved in prenatal joint formation and morphogenesis. Collagen degradation products in urine and mutation analysis of PLOD2 may be used to diagnose BS and differentiate it from OI.

Abnormalities, Multiple↗
PubMed2004

Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1.

The term "spondyloperipheral dysplasia" (SPD) has been applied to the unusual combination of platyspondyly and brachydactyly as observed in a small number of individuals. The reported cases show wide clinical variability and the nosologic status and spectrum of this condition are still ill defined. Zabel et al. [1996: Am J Med Genet 63(1):123-128] reported an individual with short stature and SPD who was heterozygous for a frameshift mutation in the C-propeptide domain of COL2A1. To explain the additional finding of brachydactyly that is not an usual feature of the type II collagenopathies, it was postulated that the nature of the mutation induced precocious calcification and premature fusion of metacarpal and phalangeal growth plates. The C-propeptide of collagen II had previously been found to promote calcification ("chondrocalcin"). We have ascertained two further individuals with clinical and radiological findings of a type II collagenopathy in infancy who developed brachydactyly type E like changes of fingers and toes in childhood. In both individuals, heterozygosity for novel, distinct mutations in the C-propeptide coding region of COL2A1 were found. Although all three mutations (the one previously reported and the two novel ones) predict premature termination, their location close to the 3'-end of the mRNA probably protects them from nonsense-mediated decay and allows for synthesis of mutant procollagen chains. However, loss of crucial cysteine residues or other sequences essential for trimerization prevents these chains from associating and participating in procollagen helix formation, and thus leads to accumulation in the ER-consistent with EM findings. The mechanism leading to precocious fusion of phalangeal epiphyses remains to be explored. The consistency of clinical, radiographic, and molecular findings in these three unrelated individuals confirms SPD as a distinct nosologic entity. The diagnosis of SPD is suggested by the appearance of brachydactyly in a child who has clinical and radiographic features of a collagen II disorder.

Calcium-Binding Proteins↗
PubMed2004

Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.

Codon, Terminator↗
PubMed2004

Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.

Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) has suggested that SWS and SJS2 could be allelic disorders. Through studying a series of 19 families with SWS/SJS2, we have mapped the disease gene to chromosome 5p13.1 at locus D5S418 (Zmax=10.66 at theta =0) and have identified null mutations in the leukemia inhibitory factor receptor (LIFR or gp190 chain) gene. A total of 14 distinct mutations were identified in the 19 families. An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region. It is interesting that 12/14 mutations predicted premature termination of translation. Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells. We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.

Base Sequence↗
PubMed2003

Glutaric aciduria type 1 and neonatal screening: time to proceed--with caution.

The new technology of tandem mass spectrometry is having a significant impact on the diagnostics of inborn metabolic errors. One of the most important aspects of this new technology is the possibility of recognising a whole class of disorders within a single analytical step. Shall this powerful technology be applied to the screening of newborn babies? Careful evaluation of every single disorder that could potentially be identified is needed. In the following, I will present some considerations that concern glutaric aciduria type 1 (MIM 231670; glutaryl-CoA dehydrogenase deficiency).

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene result in a family of skeletal dysplasias, which comprise lethal (achondrogenesis type 1B and atelosteogenesis type 2) and non-lethal conditions (diastrophic dysplasia and recessive multiple epiphyseal dysplasia (rMED)). The most frequent mutation is R279W, which in a homozygous state results in rMED with bilateral clubfoot, MED, and "double layered" patella. We describe three patients with rMED caused by a previously unreported homozygous mutation in the DTDST gene. The three patients (from two families) were born to healthy, non-consanguineous parents. All developed signs of hip dysplasia in early childhood and two had episodes of recurrent patella dislocation. Two underwent bilateral total hip replacements at ages 13 and 14 years. The feet, external ears, and palate were normal. Stature was normal in all cases. Radiographs showed dysplastic femoral heads, mild generalized epiphyseal dysplasia, abnormal patella ossification, and normal hands and feet. Direct sequence analysis of genomic DNA demonstrated a homozygous 1984T > A (C653S) change in the DTDST gene in all patients. The clinically normal parents were heterozygous for the change. This is the first description of a homozygous C653S mutation of the DTDST gene. Hip dysplasia and patella hypermobility dominates the otherwise mild phenotype. These patients further expand the range of causative mutations in the DTD skeletal dysplasia family.

Adolescent↗
PubMed2003

Prenatal diagnosis of boomerang dysplasia.

Boomerang dysplasia, atelosteogenesis type 1 and Piepkorn dysplasia are bone dysplasias with an overlapping clinical spectrum characterized by deficient formation and ossification of specific elements of the skeleton. Typical symptoms include micromelia with diminished ossification, and a characteristic bowed and boomerang-like aspect of the long tubular bones. We report here a new case of boomerang dysplasia, which was detected prenatally in the 16th week of gestation by ultrasound.

Bone Diseases, Developmental↗
PubMed2003

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

Amino Acid Sequence↗
PubMed2003

Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.

UNLABELLED: A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable. CONCLUSION: as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.

Child, Preschool↗
PubMed2003

Clinical, radiographic, and genetic diagnosis of progressive pseudorheumatoid dysplasia in a patient with severe polyarthropathy.

A 14-year-old boy presented with a 10-year history of the "sicca" form of seronegative juvenile idiopathic polyarthritis. Severely limited range of motion, pain, and capsular swelling in both small and large weight-bearing joints left him wheelchair-bound. Erythrocyte sedimentation rate and C-reactive protein were normal. Two-phase bone scan revealed tracer uptake of almost every joint at both early and late time points, indicating pathologic exudation and enhanced bone metabolism consistent with severe arthritis. However, radiographic studies revealed no erosive arthropathy but severe osteopenia, dysplastic bone changes, mega os trigonum, and platyspondylia. A magnetic resonance imaging (MRI) scan of the hips showed no signs of synovitis, pannus, or effusion but cartilage irregularities and subchondral cysts. These findings strongly suggested the diagnosis of progressive pseudorheumatoid dysplasia of childhood, an autosomal-recessive disorder of cartilage homeostasis. The patient carries a novel homozygous two-nucleotide deletion in exon 4 of the WISP3 gene. This genetic disorder is an important differential diagnosis of sicca polyarthritis.

Adolescent↗
PubMed2003

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Arteries↗