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FASEB Journal : Official Publication of... Sep 2011Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1)...
Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) and is characterized by widening of the metaphyses, reduction of long bone length, and short stature. A transgenic mouse expressing this mutation under the collagen α1(II) promoter has been generated to investigate the mechanisms responsible for this chondrodysplasia. We recently identified zinc finger protein 521 (Zfp521) as a downstream target gene of PTHrP signaling. Interestingly, loss of Zfp521 from chondrocytes leads to reduced cell proliferation and increased differentiation in the growth plate. Thus, we hypothesized that specifically ablating Zfp521 from Jansen chondrocytes could sufficiently rescue the chondrodysplasia phenotype. Our results show that Zfp521 expression is up-regulated in Jansen mouse growth plate chondrocytes and that PTHR1 is required for Zfp521 expression. Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length. This study provides the first genetic evidence that Zfp521 is required downstream of PTHR1 signaling to act on chondrocyte proliferation, differentiation, and cell death.
Topics: Animals; Bone Development; Cells, Cultured; Chondrocytes; Disease Models, Animal; Gene Deletion; Gene Expression Regulation; Genotype; Growth Plate; Mice; Mice, Knockout; Osteochondrodysplasias; Phenotype; Transcription Factors; Up-Regulation
PubMed: 21642473
DOI: 10.1096/fj.11-183277 -
Studies in History and Philosophy of... Dec 2010This article discusses the Tibetan notion of rlung, usually translated as: 'wind', but perhaps better understood as a close equivalent of pneuma in the Greek tradition,...
This article discusses the Tibetan notion of rlung, usually translated as: 'wind', but perhaps better understood as a close equivalent of pneuma in the Greek tradition, or qi in the Chinese tradition. The article focuses on the way rlung provides a useful prism through which concepts of health, illness and disease may be observed in a cross-cultural perspective. An analysis of syndromes linked with rlung in a Tibetan cultural context illuminates some of the ways in which culture determines particular syndromes. The article raises a number of questions which are relevant for a more general multicultural approach to concepts of health, illness and disease. The article argues that notions of rlung/pneuma/wind/ qi constitute a particularly interesting area for an exploration of culture-bound syndromes, as they reside in the meeting point between material and non-material, physical and mental, as well as the psychological, spiritual and religious. They are hence fundamental for a more cross-cultural approach to the mind-body problem. The article also deals with the significance of history of medicine, particularly histories of medicine, which attempt to widen the scope of the traditional Eurocentric narrative of the history of medicine, in dealing with questions such as concepts of health and illness. Allowing alternative narratives-whether narratives of patients, other cultures or historical ones-can enhance our understanding of what health, illness and disease are. Discussing perceptions of the body as culturally defined is not only important from a philosophical or historical point of view, but also has important practical ramifications, which are particularly crucial in our global age.
Topics: Cross-Cultural Comparison; Culture; Disease; History of Medicine; History, Ancient; Humans; Medicine, Traditional; Mind-Body Relations, Metaphysical; Qi; Syndrome; Tibet; Wind
PubMed: 21112005
DOI: 10.1016/j.shpsc.2010.10.005 -
Journal of Bone and Mineral Research :... Feb 2013Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers....
Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and "tongues" of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial.
Topics: Adult; Bone Diseases; Child; Child, Preschool; Etidronic Acid; Female; Humans; Infant; Infant, Newborn; Male; Radiography; Vascular Calcification
PubMed: 22972716
DOI: 10.1002/jbmr.1752 -
Journal of Medical Genetics Oct 2002Dyggve-Melchior-Clausen syndrome (DMC) is an autosomal recessive condition characterised by short trunk dwarfism, scoliosis, microcephaly, coarse facies, mental...
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.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Child; Child, Preschool; Chromosomes, Human, Pair 18; Consanguinity; Dwarfism; Female; Genetic Markers; Haplotypes; Homozygote; Humans; Intellectual Disability; Limb Deformities, Congenital; Loss of Heterozygosity; Male; Pedigree; Pelvis; Physical Chromosome Mapping; Radiography; Scoliosis; Syndrome
PubMed: 12362026
DOI: 10.1136/jmg.39.10.714 -
International Orthopaedics 2003We used Magnetic resonance imaging (MRI) in five patients (six knees), mean age 13.2 (12-15) years, with late-onset tibia vara (Blount's disease), to study the growth...
We used Magnetic resonance imaging (MRI) in five patients (six knees), mean age 13.2 (12-15) years, with late-onset tibia vara (Blount's disease), to study the growth plate and its abnormalities. The MRI study was classified for severity of disease and compared with a radiographic classification. In severely involved knees, MRI indicated severe growth-plate changes on both sides of the knee joint. Widening in the entire proximal tibial growth plate, involvement of the distal femoral growth plate, as well as cartilage invaginations into the metaphyses, were constant findings. Three knees were treated operatively with oblique tibial osteotomy and three with lateral hemiepiphysiodesis. Two severely involved patients treated initially with hemiepiphysiodesis required additional surgery. The three patients with mild disease treated with tibial osteotomy had good clinical and functional results. This study suggests that extensive growth-plate changes in severe, late-onset tibia vara preclude successful treatment by tibial hemiepiphysiodesis. In addition, oblique osteotomy, which was successful in mild cases, was problematic in severe cases.
Topics: Adolescent; Bone Diseases, Developmental; Child; Growth Plate; Humans; Knee; Magnetic Resonance Imaging; Male; Obesity; Severity of Illness Index; Tibia; Treatment Outcome
PubMed: 12748828
DOI: 10.1007/s00264-003-0467-4 -
Endocrine Journal Aug 1997Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually hypercalcemia. We report a Japanese male patient with JMC who...
Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually hypercalcemia. We report a Japanese male patient with JMC who presented with rachitic signs on radiographs, hypercalcemia (13 mg/dl) and low %TRP at age 3 months (mo). Hypercalcemia was treated from age 3 mo to 11 yr. Progressive widening, splaying and fragmentation of the metaphyses have been recognized on radiographs which resulted in shortened tubular bones and consequent short stature [107 cm (-6.5 SD)] at age 13 yr. Hypercalcemia tended to normalize, and %TRP became normal at age 13 yr. Repeated measurements of serum PTH and PTH-related protein (PTHrP) levels showed that they were low or normal in the face of hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the PTH/PTHrP receptor. Direct sequencing of PTH/PTHrP receptor complementary DNA from skin fibroblast cells revealed a CAC to CGC transversion yielding a strictly conserved His223 to Arg substitution found in 90% of DNA fragment in the second transmembrane domain of the receptor. This mutation created a restriction site Sphl (G/CATG/C). Direct sequencing of genomic DNA and also restriction enzyme digestion revealed heterozygous transition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and calcium homeostasis are age-dependent in JMC, and that the His223-Arg substitution is the same as that found in four Caucasian patients with a similar phenotype irrespective of the ethnic difference, and that the preferential expression of an abnormal allele of the PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic DNA suggests the importance of allele expression.
Topics: Dwarfism; Humans; Infant, Newborn; Male; Osteochondrodysplasias; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Polymerase Chain Reaction; Proteins; RNA, Messenger; RNA-Directed DNA Polymerase; Receptors, Parathyroid Hormone; Sequence Analysis, DNA
PubMed: 9447281
DOI: 10.1507/endocrj.44.493 -
The Journal of Biological Chemistry May 2004Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the "bone-related" Runx2-II and...
Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the "bone-related" Runx2-II and non-osseous Runx2-I isoforms that differ only in their respective N termini. Existing mutant mouse models with both isoforms deleted exhibit an arrest of osteoblast and chondrocyte maturation and the complete absence of mineralized bone, but they do not distinguish the separate functions of the two N-terminal isoforms. To elucidate the function of the bone-related isoform, we generated selective Runx2-II-deficient mice by the targeted deletion of the distal promoter and exon 1. Homozygous Runx2-II-deficient (Runx2-II(-/-)) mice unexpectedly formed axial, appendicular, and craniofacial bones derived from either intramembranous ossification or mesenchymal cells of the bone collar, but they failed to form the posterior cranium and other bones derived from endochondral ossification. Heterozygous Runx2-II-deficient mice had grossly normal skeletons, but were osteopenic. The commitment of mesenchymal cells ex vivo to the osteoblast lineage occurred in Runx2-II(-/-) mice, but osteoblastic gene expression was impaired. Chondrocyte maturation appeared normal, but the zone of hypertrophic chondrocytes was not transformed into metaphyseal bone, leading to widened growth plates in Runx2-II(-/-) mice. Compensatory increments in Runx2-I expression occurred in Runx2-II(-/-) mice but were not sufficient to normalize osteoblastic maturation or transcriptional activity. Our findings support distinct functions of Runx2-II and -I in the control of skeletogenesis. Runx2-I is sufficient for early osteoblastogenesis and intramembranous bone formation, whereas Runx2-II is necessary for complete osteoblastic maturation and endochondral bone formation.
Topics: Alkaline Phosphatase; Animals; Bone and Bones; Chondrocytes; Core Binding Factor Alpha 1 Subunit; Exons; Genes, Reporter; Heterozygote; Homozygote; Mice; Mice, Mutant Strains; Models, Genetic; Neoplasm Proteins; Osteoblasts; Phenotype; Promoter Regions, Genetic; Protein Isoforms; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tomography, X-Ray Computed; Transcription Factors; Transcription, Genetic
PubMed: 15007057
DOI: 10.1074/jbc.M401109200 -
Taiwanese Journal of Obstetrics &... Jun 2012To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff).
Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice site mutation in intron 4 in the NEK1 gene.
OBJECTIVE
To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff).
CASE REPORT
A 34-year-old woman with no past history of fetal SRPS was referred to the hospital at 21 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed a narrow thorax, short ribs, short limbs with marginal spurs, and postaxial hexadactyly in both the hands and feet. A diagnosis of SRPS III (Verma-Naumoff) was made. Amniocentesis was performed. The karyotype was 46,XY. Molecular genetic analysis of the amniotic fluid cells identified a homozygous splice site mutation in intron 4 (c.331-1 A > G) or IVS4-1 A > G in the NEK1 gene. The parents were heterozygous for the mutation. The pregnancy was subsequently terminated and a malformed fetus was delivered with prominent forehead, a flattened nasal bridge, a narrow and short trunk, a protuberant abdomen, bilateral postaxial polydactyly and syndactyly of the hands and feet, and micromelic limbs. No facial cleft or genital abnormality was noted. The radiograph was consistent with SRPS III.
CONCLUSION
Polydactyly, micromelia, metaphyseal spurs, widened humeral metaphyses, and shortened ribs can be prominent prenatal ultrasound findings of SRPS III. The present case provides evidence for a correlation of a mutation in the NEK1 gene with SRPS III.
Topics: Abortion, Induced; Adult; Amniocentesis; Cell Cycle Proteins; Female; Humans; Introns; Karyotype; Male; Middle Aged; Mutation; NIMA-Related Kinase 1; Pregnancy; Pregnancy Trimester, Second; Protein Serine-Threonine Kinases; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal
PubMed: 22795106
DOI: 10.1016/j.tjog.2012.04.018 -
American Journal of Human Genetics Jun 2008We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological...
We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological findings of a mild skeletal dysplasia. The EDS-like findings comprise hyperelastic, thin, and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. The skeletal dysplasia comprises platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients have an increased ratio of total urinary pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of approximately 1 as opposed to approximately 6 in EDS VI or approximately 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl hydroxylase and prolyl 4-hydroxylase activities; underhydroxylation was a generalized process as shown by mass spectrometry of the alpha1(I)- and alpha2(I)-chain-derived peptides of collagen type I and involved at least collagen types I and II. A genome-wide SNP scan and sequence analyses identified in all patients a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. We hypothesize that an increased Zn(2+) content inside the endoplasmic reticulum competes with Fe(2+), a cofactor that is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. These data suggest an entity that we have designated "spondylocheiro dysplastic form of EDS (SCD-EDS)" to indicate a generalized skeletal dysplasia involving mainly the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the EDS-like features.
Topics: Adult; Amino Acid Sequence; Amino Acids; Base Sequence; Cation Transport Proteins; Child; Child, Preschool; Collagen; Consanguinity; DNA; Ehlers-Danlos Syndrome; Female; Genes, Recessive; Haplotypes; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Sequence Deletion; Sequence Homology, Amino Acid
PubMed: 18513683
DOI: 10.1016/j.ajhg.2008.05.001 -
Human Molecular Genetics Mar 2011Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from...
Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from neurological symptoms due to obstruction of cranial foramina. No proven treatment is available and the pathophysiology is largely unknown. A Phe377 (TTC(1130-1132)) deletion in exon 9 of the pyrophosphate (PPi) transporter ANK leads to CMD-like features in an Ank(KI/KI) mouse model. Here, we investigated the effects of CMD-mutant ANK on mineralization and bone mass at a cellular level. Ank(KI/KI) osteoblast cultures showed decreased mineral deposition. Expression of bone mineralization regulating genes Mmp13, Ocn, Osx and Phex was reduced in Ank(KI/KI) osteoblasts, while the Fgf23 mRNA level was highly elevated in Ank(KI/KI) calvarial and femoral bones. Since ANK is a known PPi transporter, we examined other regulators of Pi/PPi homeostasis Enpp1 and Tnap. Significantly increased ENPP1 activity may compensate for dysfunctional mutant ANK leading to comparable extracellular PPi levels in Ank(+/+) osteoblasts. Similar to Ank(KI/KI) bone marrow-derived macrophage cultures, peripheral blood cultures from CMD patients exhibited reduced osteoclastogenesis. Cell-autonomous effects in Ank(KI/KI) osteoclasts resulted in disrupted actin ring formation and cell fusion. In addition, Ank(KI/KI) osteoblasts failed to adequately support osteoclastogenesis. Increased bone mass could partially be rescued by bone marrow transplants supporting our hypothesis that reduced osteoclastogenesis contributes at least in part to hyperostosis. We conclude that the Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype.
Topics: Animals; Bone Diseases, Developmental; Calcification, Physiologic; Case-Control Studies; Cell Differentiation; Cells, Cultured; Craniomandibular Disorders; Disease Models, Animal; Exons; Facial Paralysis; Female; Fibroblast Growth Factor-23; Gene Expression Regulation, Developmental; Humans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Phosphate Transport Proteins; Sequence Deletion; Skull
PubMed: 21149338
DOI: 10.1093/hmg/ddq541