Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0700208 (scoliosis)
 8,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We reported a case of a fifteen-year-old boy with metatropic dysplasia. He showed short-limbed dwarfism at the age of 1 year and 2 months. Roentgenograms of the bone revealed generalized platyspondyly, enlargement of the epiphyseal-metaphyseal regions of long bones and halberd-shaped pelvis. Scoliosis progressed and he evolved to short-trunk dwarfism. When he was 10 years old, he developed gait disturbance gradually due to muscle weakness of lower extremities. He was examined at the age of 15 years. Motor nerve conduction velocity was reduced to 21 m/sec in left median nerve and 18.5 m/sec in left peroneus nerve. Needle EMG showed neurogenic pattern. We performed sural nerve biopsy and obtained histopathological findings. Fiber density of myelinated axons decreased. Electron microscopic examination revealed onion bulb formation surrounding a myelinated fiber and a storage in the rough-surfaced endoplasmic reticulum of Schwann cell. These inclusions were similar to those of cartilage of his long bone. We supposed that the neuropathy would have relation to this bone dysplasia.
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PMID:[A case of motor and sensory neuropathy associated with metatropic dysplasia]. 818 80

We describe a male patient with osteogenesis imperfecta (OI) who was born with contractures of the knee, elbow and ankle joints. During the first 4 years he suffered from recurrent fractures. He has white sclerae, mild dentinogenesis imperfecta, multiple wormian bones, severe scoliosis and short stature. Morphological analysis of cortical bone revealed typical characteristics of OI including varying width of the osteoid, swollen mitochondria and a dilated endoplasmic reticulum of the osteoblasts. Collagen fibrils of the osteoid had a varying diameter, a feature not found in typical OI patients. Analysis of compact bone showed that the size of apatite crystals and the extractability of collagen with pepsin were markedly elevated compared to controls and other OI type III and IV patients. Lysyl hydroxylation of collagen from the organic bone matrix and the electrophoretic mobility of collagen alpha 1(I)- and alpha 2(I)-chains were normal. Our results provide evidence that this patient belongs to a subtype of OI. The biochemical studies indicate that the underlying defect involves defective fibril-formation of collagen type I leading to an altered mineralization of bone.
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PMID:Defective collagen fibril formation and mineralization in osteogenesis imperfecta with congenital joint contractures (Bruck syndrome). 833 19

Dyggve-Melchior-Clausen syndrome (DMC) is an autosomal recessive condition characterised by short trunk dwarfism, scoliosis, microcephaly, coarse facies, mental retardation, and characteristic radiological features. X rays show platyspondyly with double vertebral hump, epiphyseal dysplasia, irregular metaphyses, and a characteristic lacy appearance of the iliac crests. Electron microscopy of chondrocytes have shown widened cisternae of rough endoplasmic reticulum and biochemical analyses have shown accumulation of glucosaminoglycan in cartilage, but the pathogenesis of DMC remains unexplained. Here, we report on the homozygosity mapping of a DMC gene to chromosome 18q21.1 in seven inbred families (Zmax=9.65 at theta=0 at locus D18S1126) in the genetic interval (1.8 cM) defined by loci D18S455 and D18S363. Despite the various geographical origins of the families reported here (Morocco, Tunisia, Portugal, and Lebanon), this condition was genetically homogeneous in our series. Continuing studies will hopefully lead to the identification of the disease causing gene.
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PMID:Homozygosity mapping of a Dyggve-Melchior-Clausen syndrome gene to chromosome 18q21.1. 1236 26

The aetiology of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, is unclear. Previous studies showed controversial platelet abnormalities including intracellular calcium. Platelet Ca2+ homeostasis is controlled by a multi-Ca2+-ATPase system including SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) and PMCA (plasma membrane Ca2+-ATPase) isoforms. Here, we first investigated the expression of PMCA4b, SERCA3a and SERCA2b isoforms in platelets of 17 patients with AIS. Patients presenting thoracic curves were found to present a higher PMCA4b expression coupled to a lower SERCA3a one in agreement with an abnormality in platelet maturation. Indeed, using PMA-treated MEG 01 cells, an in vitro model of megakaryocytopoiesis, we found an increase in SERCA3a expression, associated to a caspase-3 mediated C terminal proteolysis of PMCA4b. To look whether platelets reflect a basic defect in cell differentiation, we next identified osteoblast Ca2+-ATPases and studied their expressions in AIS. Major expressions of PMCA4b and SERCA2b were found in normal osteoblasts. Comparing platelets and osteoblasts in two additional patients with AIS, we found opposite and concerted regulations of the expressions of PMCA4b and caspase-3 substrate, PARP in both cell types. A systemic defect in cell differentiation involving caspase-3 can be proposed as a novel mechanism in the etiopathogenesis of the most frequent type of AIS. *R. Bredoux and E. Corvazier contributed equally to this work.
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PMID:Human platelet Ca2+-ATPases: new markers of cell differentiation as illustrated in idiopathic scoliosis. 1697 4

Our objective was to investigate whether dynamic tensile strain on previously compressed human intervertebral disc (IVD) cells can restore the biosynthetic effects of collagen and glycosaminoglycan. Inner annulus fibrosus (AF) and nucleus pulposus (NP) tissues of adolescent idiopathic scoliosis cases undergoing thoracoscopic discectomy and fusion were cultured on compressive plates. Compressive stress was applied using 0.4 MPa at 1 Hz, for 2 h twice a day for 7 days, to the inner AF and NP tissues, followed by equibiaxial cyclic tensile strain to deform the released cells onto the plate's flexible bottom. With 10% elongation at a rate of 1 Hz, for 2 h twice a day for 7 days, a significant increase in the level of collagen and glycosaminoglycan of the previously compressed inner AF, as well as the level of glycosaminoglycan of the previously compressed NP cells were found. The DNA content and number of endoplasmic reticulum under transmission electron micrograph of the previously compressed inner AF and NP cell were also significantly increased. The results suggested that equibiaxial cyclic tensile strain at a rate of 1 Hz with 10% tensile strain was capable of increasing collagen and glycosaminoglycan synthesis of previously compressed inner AF cells, and glycosaminoglycan synthesis of previously compressed NP cells.
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PMID:Effects of cyclic dynamic tensile strain on previously compressed inner annulus fibrosus and nucleus pulposus cells of human intervertebral disc-an in vitro study. 1981 Jan 4

Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.
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PMID:Identification of CANT1 mutations in Desbuquois dysplasia. 1985 39

Defects leading to impaired intracellular trafficking have recently been shown to play an important role in the pathogenesis of genodermatoses, such as the Ehlers-Danlos and the cutis laxa syndromes. A new genodermatosis, termed macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome has been described, resulting from a homozygous 1-bp deletion in RIN2. RIN2 encodes the Ras and Rab interactor 2, involved in the regulation of Rab5-mediated early endocytosis. We performed a clinical, ultrastructural and molecular study in a consanguineous Algerian family with three siblings affected by a distinctive autosomal recessive genodermatosis, reported in 2005 by Verloes et al. The most striking clinical features include progressive facial coarsening, gingival hypertrophy, severe scoliosis, sparse hair and skin and joint hyperlaxity. Ultrastructural studies of the skin revealed important abnormalities in the collagen fibril morphology, and fibroblasts exhibited a dilated endoplasmic reticulum and an abnormal Golgi apparatus with rarefied and dilated cisternae. Molecular analysis of RIN2 revealed a novel homozygous 2-bp deletion in all affected individuals. The c.1914_1915delGC mutation introduces a frameshift and creates a premature termination codon, leading to nonsense-mediated mRNA decay. These findings confirm that RIN2 defects are associated with a distinct genodermatosis and underscore the involvement of RIN2 and its associated pathways in the pathogenesis of connective tissue disorders. The current family displays considerable phenotypic overlap with MACS syndrome. However, our family shows a dermatological and ultrastructural phenotype belonging to the Ehlers-Danlos rather than the cutis laxa spectrum. Therefore, the MACS acronym is not entirely appropriate for the current family.
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PMID:The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2). 2042 61

We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.
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PMID:Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. 2226 13

Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1-related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the Sepn1 knock-out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1-related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1-related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options.
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PMID:Selenoprotein N in skeletal muscle: from diseases to function. 2252 82

NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype.
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PMID:Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations. 2570 56


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