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Biomedical subjects

D Krakow

Publications and source records attributed to D Krakow.

At least 19 recordsLinked to original sources
PubMed2005

Mutations in FLNB cause boomerang dysplasia.

Boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome that we have recently shown to be associated with mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. We report the identification of mutations in FLNB in two unrelated individuals with boomerang dysplasia. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans.

Abnormalities, Multiple↗
PubMed2004

A locus for spondylocarpotarsal synostosis syndrome at chromosome 3p14.

Spondylocarpotarsal synostosis syndrome is a rare autosomal recessive disorder characterised by vertebral fusions, frequently manifesting as an unsegmented vertebral bar, as well as fusions of the carpal and tarsal bones. In a study of three consanguineous families and one non-consanguineous family, linkage analysis was used to establish the chromosomal location of the disease gene. Linkage analysis localised the disease gene to chromosome 3p14. A maximum lod score of 6.49 (q = 0) was obtained for the marker at locus D3S3532 on chromosome 3p. Recombination mapping narrowed the linked region to the 5.7 cM genetic interval between the markers at loci D3S3724 and D3S1300. A common region of homozygosity was found between the markers at loci D3S3724 and D3S1300, defining a physical interval of approximately 4 million base pairs likely to contain the disease gene. Identification of the gene responsible for this disorder will provide insight into the genes that play a role in the formation of the vertebral column and joints.

Carpal Bones↗
PubMed2003

Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias.

OBJECTIVE: Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases. METHODS: We studied five women with fetuses of 16-28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared. RESULTS: The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities. CONCLUSION: The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy.

Bone Diseases, Developmental↗
PubMed2001

Identification of human FEM1A, the ortholog of a C. elegans sex-differentiation gene.

We report the isolation, genomic structure, chromosomal location, and expression pattern of the FEM1A gene, the human ortholog of the Caenorhabditis elegans fem-1 and mouse Fem1a genes. The coding sequence is 1851 bp and encodes a 617 amino acid protein. The human FEM1A protein has 65% identity with the mouse Fem1a protein and 34% identity with the C. elegans fem-1 protein, indicating conservation of this protein. The N-terminal region of the encoded protein contains six ankyrin repeat elements, a motif found in signaling and transcriptional regulatory molecules such as Notch and glp1. The gene was highly expressed in human kidney and cardiac tissue, and was expressed at lower levels in multiple tissues, including cartilage. FEM1A was localized to chromosome 5q23.1, a region of conserved synteny with a portion of mouse chromosome 17 that contains Fem1a. In C. elegans, fem-1 is involved in a pathway necessary for sex determination. The identification of a human homolog of this conserved gene suggests a potential role for this sex-determining molecule in humans.

Amino Acid Sequence↗
PubMed2001

Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita.

Pseudoachondroplasia (PSACH) and spondyloepiphyseal dysplasia congenita (SEDC) are autosomal dominant forms of short-limb short stature caused by mutations in genes that encode structural components of the cartilage extracellular matrix. PSACH results from mutations in the cartilage oligomeric matrix protein (COMP) gene, while SEDC is caused by mutations in the gene for type II procollagen (COL2A1). We report a child with a distinct skeletal dysplasia due to the combined phenotypes of PSACH and SEDC. The proband's mother had PSACH and his father had SEDC. The child was suspected of having both phenotypes on the basis of the severity of his clinical and radiographic findings, and this was confirmed by molecular analysis. The COMP gene mutation (C348R), while not previously published, is typical of those in PSACH patients, whereas the COL2A1 mutation (T1370M) is somewhat atypical, as it predicts an amino acid change within the carboxyl-terminal region of the protein. Both mutations segregated with their respective phenotypes within this family. The description and natural history of the double heterozygote phenotype may be useful in counseling families regarding risk and prognosis.

Achondroplasia↗
PubMed2001

Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism.

Acrodysostosis is an uncommon skeletal dysplasia associated with nasal hypoplasia, midface deficiency, severe brachydactyly, and varying degrees of hearing loss and mental retardation. Previous publications have suggested that it may be difficult to distinguish acrodystostosis from pseudohypoparathyroidism on clinical grounds, but acrodysostosis does appear to have distinct clinical and radiologic findings. Spinal stenosis is an underappreciated risk in acrodysostosis, despite the reported loss of normal caudal widening of the lumbar interpediculate distance on AP spine radiographs in the original report of this disorder by Robinow et al., with confirmation of these radiographic findings by Butler et al. We report two sporadic cases of acrodysostosis, one of which required decompressive laminectomy for symptomatic spinal stenosis, and review 11 cases of acrodysostosis from 9 families that were submitted to the International Skeletal Dysplasia Registry. The objective of this report is to determine the frequency and severity of spinal stenosis in patients with acrodysostosis and to summarize the clinical and radiographic findings of acrodysostosis in an effort to distinguish acrodysostosis clearly from pseudohypoparathyroidism. The pattern of brachydactyly differs between these two conditions, and varying degrees of spinal stenosis are characteristic of acrodysostosis. Both our index patients with acrodysostosis had normal bioactivity of the alpha subunit of the Gs protein, therefore indicating that acrodysostosis has a different pathogenesis from pseudohypoparathyroidism. Furthermore, single-strand confirmational polymorphism (SSCP) analysis failed to demonstrate any confirmational alterations in the coding exons of the Gs alpha gene. These radiographic and laboratory findings substantiate that acrodysostosis is clinically different from pseudohypoparathyroidism and that it is necessary to follow patients with acrodysostosis for signs of spinal stenosis.

Dysostoses↗
PubMed2000

Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis.

The COL2A1 gene was assayed for mutations in genomic DNA from 12 patients with achondrogenesis type II/hypochondrogenesis. The exons and flanking sequences of the 54 exons in the COL2A1 gene were amplified by a series of specific primers using PCR. The PCR products were scanned for mutations by conformation sensitive gel electrophoresis, and PCR products that generated heteroduplex bands were then sequenced. Mutations in the COL2A1 gene were found in all 12 patients. Ten of the mutations were single base substitutions that converted a codon for an obligate glycine to a codon for an amino acid with a bulkier side chain. One of the mutations was a change in a consensus RNA splice site. Another was an 18-base pair deletion of coding sequences. The results confirmed previous indications that conformation sensitive gel electrophoresis is highly sensitive for detection of mutations in large and complex genes. They also demonstrate that most, if not all, patients with achondrogenesis type II/hypochondrogenesis have mutations in the COL2A1 gene.

Amino Acid Substitution↗
PubMed2000

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↗
PubMed2000

Femur length and trisomy 21: impact of gestational age on screening efficiency.

OBJECTIVE: This study assesses two methods used to define relatively short femur in screening for trisomy 21 and examines changes in performance of screening with gestational age. DESIGN: Retrospective analysis of data on menstrual age, femur length (FL) and biparietal diameter (BPD) in 49 trisomy 21 pregnancies and 6069 normal controls. Reference ranges were derived for BPD/FL versus menstrual age and for FL versus BPD. Two methods of defining short femur (BPD/FL and observed-to-expected FL ratio) were examined for false-positive rates and detection rates for trisomy 21 at different gestational ages. RESULTS: In the control group the BPD/FL ratio and its standard deviation decreased with menstrual age. Trisomy 21 was associated with a significantly higher BPD/FL ratio (P < 0.001) and the deviation increased significantly with menstrual age (P < 0.05). Eleven percent of 28 fetuses examined at 15-17 weeks had a BPD/FL above the 95th centile compared with 24% of 21 fetuses examined at 18-20 weeks (P = 0.40). The median observed-to-expected FL ratio in the control group was 1.0 throughout the gestational age range but the standard deviation decreased significantly with menstrual age (P < 0.01). Trisomy 21 was associated with a significantly reduced observed-to-expected FL ratio (P < 0.001) and the deviation increased significantly with menstrual age (P < 0.05). A fixed cut-off of 0.91 for observed-to-expected FL ratio provided a false-positive rate of 12% at 15-17 weeks compared with 6% at 18-20 weeks of gestation (P < 0.001) with detection rates of 29 and 38%, respectively (P = 0.73). CONCLUSION: Irrespective of the definition used to define the condition, relatively short femur is a poor marker for trisomy 21 particularly when the assessment takes place before 18 weeks of gestation.

Adult↗
PubMed1999

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Abnormalities, Multiple↗
PubMed1999

Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene.

Ehlers-Danlos syndrome (EDS) type VIIC is a recessively inherited connective-tissue disorder, characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical hernia, and blue sclera. Like the animal model dermatosparaxis, EDS type VIIC results from the absence of activity of procollagen I N-proteinase (pNPI), the enzyme that excises the N-propeptide of type I and type II procollagens. The pNPI enzyme is a metalloproteinase containing properdin repeats and a cysteine-rich domain with similarities to the disintegrin domain of reprolysins. We used bovine cDNA to isolate human pNPI. The human enzyme exists in two forms: a long version similar to the bovine enzyme and a short version that contains the Zn++-binding catalytic site but lacks the entire C-terminal domain in which the properdin repeats are located. We have identified the mutations that cause EDS type VIIC in the six known affected human individuals and also in one strain of dermatosparactic calf. Five of the individuals with EDS type VIIC were homozygous for a C-->T transition that results in a premature termination codon, Q225X. Four of these five patients were homozygous at three downstream polymorphic sites. The sixth patient was homozygous for a different transition that results in a premature termination codon, W795X. In the dermatosparactic calf, the mutation is a 17-bp deletion that changes the reading frame of the message. These data provide direct evidence that EDS type VIIC and dermatosparaxis result from mutations in the pNPI gene.

Alternative Splicing↗
PubMed1998

Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred.

We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings.

Abnormalities, Multiple↗
PubMed1998

Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia.

Various mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have recently been reported in thanatophoric dysplasia (TD). We examined the clinical, radiographic, and histologic findings in 91 cases from the International Skeletal Dysplasia Registry and correlated them with the specific FGFR3 mutation. Every case of TD examined had an identifiable FGFR3 mutation. Radiographically, all of the cases with the Lys650Glu substitution demonstrated straight femora with craniosynostosis, and frequently a cloverleaf skull (CS) was demonstrated. In all other cases, the femora were curved, and CS was infrequently present but was occasionally as severe as TD with the Lys650Glu substitution. Histopathologically, all of the cases shared similar abnormalities, but cases with the Lys650Glu substitution had better preservation of the growth plate. Cases with the Tyr373Cys substitution tended to have more severe radiographic manifestations than the Arg248Cys cases, but there was overlap in the phenotypic spectrum between them. One common classification of TD distinguishes affected infants based on the presence or absence of CS. In contrast, and as originally proposed by Langer et al. [1987: Am J Med Genet 3: 167-179], our data suggest that TD can be divided into at least two groups (TD1 and TD2) based on the presence of straight or curved femora. The variable presence of CS and severity of the radiologic and histologic findings in the other substitutions may be due to other genetic, environmental, or stochastic factors.

Chondrocytes↗
PubMed1998

Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse.

The osteochondrodysplasias are a genetically heterogeneous group of disorders affecting skeletal development, linear growth and the maintenance of cartilage and bone. We have studied a large inbred Pakistani family with a distinct form of recessively inherited spondyloepimetaphyseal dysplasia (SEMD) and mapped a gene associated with this dwarfing condition to chromosome 10q23-24, a region syntenic with the locus for the brachymorphic mutation on mouse chromosome 19. We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes. We characterized a nonsense mutation in ATPSK2 in the SEMD family and a missense mutation in the region of Atpsk2 encoding the APS kinase activity in the brachymorphic mouse. ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell types. The cartilage-specificity of the human and mouse phenotypes provides further evidence of the critical role of sulfate activation in the maturation of cartilage extracellular matrix molecules and the effect of defects in this process on the architecture of cartilage and skeletogenesis.

Amino Acid Sequence↗
PubMed1998

Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.

Multiple synostoses syndrome is an autosomal dominant disorder characterized by premature onset of joint fusions, which initially affect the interphalangeal joints, by characteristic facies, and by deafness. We performed linkage analysis on a large Hawaiian family with multiple synostoses syndrome. Because another autosomal dominant disorder, proximal symphalangism, shares some clinical symptoms with multiple synostoses syndrome and has been linked to markers at loci at chromosome 17q21-22, we tested the hypothesis that multiple synostoses syndrome is linked to the same chromosomal region. Using polymorphic markers from the proximal symphalangism interval, we conducted linkage analysis and showed that the multiple synostoses-syndrome phenotype is linked to the same chromosomal region. A maximum LOD score of 3.98 at recombination fraction of .00 was achieved for the marker at locus D17S787. Further genetic analysis identified individuals with recombinant genotypes, allowing localization of the disease gene within the interval D17S931-D17S792, a 16-cM region. These data provide evidence that multiple synostoses syndrome and proximal symphalangism may be allelic disorders.

Abnormalities, Multiple↗
PubMed1994

Effect of hemodialysis on uterine and umbilical artery Doppler flow velocity waveforms.

A case of a pregnant woman with membranous glomerulonephropathy requiring hemodialysis is described. During hemodialysis the patient underwent Doppler flow studies of the uterine and umbilical arteries. In spite of avoidance of hypotension and major fluid shifts, hemodialysis was accompanied by a significant increase in the systolic/diastolic ratio of the proximal uterine artery. There was no significant change in the umbilical artery systolic/diastolic ratio.

Adult↗
PubMed1994

Genetic aspects of ovarian cancer.

Ovarian cancer continues to be the foremost cause of mortality because of gynecologic malignancies. Surgical and chemotherapeutic advances have been made, yet the cause of ovarian oncogenesis is poorly understood. Recognition of the familial clustering has focused investigators in the direction of isolating genetic susceptibility loci for ovarian cancer. Research on cytogenetic abnormalities have led to the identification of oncogenes and tumor suppressor genes, which have contributed to a multistep model of molecular oncogenesis. This review discusses how the familial clustering of breast and ovarian cancers, as well as the chromosomal alterations and oncogenes identified, have all contributed to our understanding of the genetic factors involved in the development of ovarian cancer.

Cluster Analysis↗