Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. (1/42)

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.  (+info)

Prenatal sonographic features of spondylocostal dysostosis and diaphragmatic hernia in the first trimester. (2/42)

Spondylocostal dysostosis is a congenital disorder characterized by multiple malformations of the vertebrae and ribs. We describe the sonographic features of an affected fetus at 12 and 14 weeks of gestation. The fetus had thoracic scoliosis, multiple vertebral and rib malformations and a grossly dilated stomach that had herniated into the chest through a left-sided diaphragmatic hernia. The stomach spanned the whole length of the fetal trunk.  (+info)

A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3. (3/42)

In spondylocostal dysostosis (SD), vertebral-segmentation defects are associated with rib anomalies. This results in short-trunk short stature, nonprogressive kyphoscoliosis, and radiological features of multiple hemivertebrae and rib fusions. SD can be familial, and both autosomal dominant and autosomal recessive (AR) inheritance have been reported, but no genes have been identified or localized for nonsyndromic SD in humans. We performed genomewide scanning by homozygosity mapping in a large consanguineous ARSD Arab Israeli family with six definitely affected members. Significant linkage was found to chromosome 19q13, with a LOD score of 6.9. This was confirmed in a second Pakistani family with three affected members, with a LOD score of 2.4. The combined-haplotype data identify a critical region between D19S570 and D19S908, an interval of 8.5 cM on 19q13.1-19q13.3. This is the first study to localize a gene for nonsyndromic SD. ARSD is clinically heterogeneous and is likely to result from mutations in developmental genes or from regulating transcription factors. Identification of these genes will improve the understanding of the molecular processes contributing to both normal and abnormal human vertebral development.  (+info)

Shwachman-Diamond syndrome: An inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. (4/42)

Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant myeloid transformation, is an important model for understanding genetic determinants in hematopoiesis. To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34(+) cells on bone marrow aspirates. SD CD34(+) cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34(+) cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34(+) cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.  (+info)

Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. (5/42)

The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.  (+info)

Tethered cord in a patient with multiple vertebral segmentation defects: a case report. (6/42)

Short trunk dwarfism with multiple vertebral segmentation defects (MVSD) represents a heterogeneous group of disorders characterized by the presence of multiple vertebral and rib abnormalities. A two and one-half year-old female with the spondylothoracic dysostosisform of MVSD is presented. In addition to skeletal anomalies, a lumbar hemangioma, bilateral foot deformities, distal leg atrophy and weakness, and areflexia at the ankles were present. An underlying neuropathic process was suspected. Results of urodynamic studies were suggestive of a neurogenic bladder. Magnetic resonance imaging of the spine demonstrated a tethered spinal cord. Although various brain and spinal cord anomalies have been described in MVSD, this is the first reported case, to our knowledge, of a tethered spinal cord in a patient with MVSD. We recommend that the management of patients with MVSD include comprehensive neurological evaluation and monitoring with appropriate electrodiagnostic, urodynamic, and neuroimaging studies.  (+info)

Notch signaling and inherited disease syndromes. (7/42)

The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in organisms as diverse as insects, nematodes, echinoderms and mammals. Disruptions in conserved developmental pathways frequently result in inherited congenital anomalies in humans. Mutations in genes encoding Notch pathway components underlie three inherited human diseases: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mouse models for these three diseases have been developed, and are leading to novel insights into the pathology of these diseases in humans.  (+info)

Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. (8/42)

The spondylocostal dysostoses (SCD) are a group of disorders characterised by multiple vertebral segmentation defects and rib anomalies. SCD can either be sporadic or familial, and can be inherited in either autosomal dominant or recessive modes. We have previously shown that recessive forms of SCD can be caused by mutations in the delta-like 3 gene, DLL3. Here, we have sequenced DLL3 in a series of SCD cases and identified 12 mutations in a further 10 families. These include 10 novel mutations in exons 4-8, comprising nonsense, missense, frameshift, splicing, and in frame insertion mutations that are predicted to result in either the truncation of the mature protein in the extracellular domain, or affect highly conserved amino acid residues in the epidermal growth factor-like repeats of the protein. The affected cases represent diverse ethnic backgrounds and six come from traditionally consanguineous communities. In all affected subjects, the radiological phenotype is abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which we suggest the term "pebble beach sign". This is a very consistent phenotype-genotype correlation and we suggest the designation SCD type 1 for the AR form caused by mutations in the DLL3 gene.  (+info)

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