Report of the Fifth International Workshop on Human Chromosome 11 Mapping 1996.
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Chromosome Mapping↗
Biomedical subjects
B Zabel
Publications and source records attributed to B Zabel.
Human CLAPS2 encoding AP17, a small chain of the clathrin-associated protein complex: cDNA cloning and chromosomal assignment to 19q13.2-->q13.3.
We have cloned the cDNA for the human homolog of the rat AP17 gene, a small chain of the clathrin-associated protein complex AP-2. The cDNA is highly conserved between rat and human. Human AP17, gene symbol CLAPS2 (clathrin-associated/assembly/adaptor protein, small 3, 17 kDa), was assigned to chromosome region 19q13.2-->q13.3.
Adaptor Protein Complex 2↗
Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11.
A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of approximately 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.
Abnormalities, Multiple↗
Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.
Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM interval between D11S1298 and D11S971 and most likely lies in a 3-cM region between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with OPS.
Alleles↗
Developmental expression of splicing variants of fibroblast growth factor receptor 3 (FGFR3) in mouse.
A characteristic feature of the fibroblast growth factor receptor (FGFR) family is the structural diversity generated by alternative splicing. The FGFR3 gene encodes two splice variants because of the mutually exclusive use of the exons IIIb and IIIc. In the present study we examined the expression of the two different splice forms IIIb and IIIc of FGFR3 in developing mouse embryos (12 days p.c., 14 days p.c., 20 days p.c.). The overall level of the IIIc exon splice product surpassed that of the IIIb exon form. The IIIc mRNA was detected in the developing brain and in the spinal cord. Outside the nervous system very strong expression was observed in the vertebra and in all other bony structures. In contrast, the IIIb splice form was restricted to epithelial structures with no expression detected in the central nervous system and bone.
Alternative Splicing↗
Systematic screening of an arrayed cDNA library by PCR.
We have developed a PCR-based method for rapid and effective screening of arrayed cDNA libraries. This strategy directly addresses the limitations of conventional hybridization-based schemes and provides a more rapid, cost-effective, and sensitive method compatible with large-scale and routine cDNA clone recovery. To prepare arrayed libraries, 1-2 x 10(6) cDNA clones were propagated as individual plaques on solid medium in 24-well culture dishes at approximately 250 plaque-forming units per well. Phage suspensions were prepared from each well and transferred to a 96-well format. To screen the library, pools were generated that correspond to each individual 96-well plate and to each row and column within "blocks" of six plates each. Library screening for specific cDNA clones was conducted in a systematic and hierarchical fashion beginning with the plate pools. Next, the row/column pools corresponding to each positive plate pool were screened. Finally, isolated clones from within each positive well were identified by hybridization. We have applied this approach to the screening of an arrayed human brain cDNA library resulting in the recovery of cDNAs corresponding to > 25 genes and expressed sequence tags.
Adult↗
Non-radioactive multiplex-SSCP analysis: detection of a new type II procollagen gene (COL2A1) mutation.
We have developed a protocol that allows fast and efficient mutation screening of the 54 exons from the type II procollagen (COL2A1) gene. The protocol is based on the multiple non-radioactive hybridization of blotted single-strand conformation polymorphism gels. Using this screening procedure we have been able to identify a new (Gly895 to Ser) mutation in the COL2A1 gene of a patient with a mild form of spondyloepiphyseal dysplasia congenita.
Amino Acid Sequence↗
Nephropathy with Wilms tumour or gonadal dysgenesis: incomplete Denys-Drash syndrome or separate diseases?
UNLABELLED: We report three children, one presenting with nephropathy, bilateral Wilms tumour (WT) and cryptorchism, one with combined nephropathy and gonadal dysgenesis and one with nephropathy which developed 13 years after a WT. The first case was recognized as typical Denys-Drash syndrome (DDS) which is characterized by the combination of nephropathy, intersex disorders and WT. The two other patients, who did not express the full spectrum of the syndrome, were older than 10 years, when they reached and stage renal failure. The fact that nephropathy in childhood is combined with such rare diseases like gonadal dysgenesis and/or WT, supports the concept of a common aetiology with DDS. Therefore, the patients were analysed for possible Wilms tumour suppressor gene (WT1) mutations. In all three individuals mutations in the heterozygous configuration could be demonstrated. CONCLUSION: These results provide evidence that incomplete and complete DDS are diseases of the same spectrum. WT1 analysis of more children with two symptoms of the triad of DDS should be helpful in establishing genotype-phenotype correlations and in understanding differences in the clinical picture of DDS.
Adolescent↗
Phenotypic variability in patients with generalised resistance to thyroid hormone.
Genetic linkage of generalised resistance to thyroid hormone (GRTH) to the human thyroid receptor beta 1 gene has been identified. To date 38 different mutations in several kindreds have been documented. We report on a family with GRTH displaying an adenine for guanine substitution at nucleotide 1234 resulting in a threonine for alanine substitution at codon 317 of exon 9. This mutation has been described for different phenotypes, suggesting that the heterogeneity in GRTH may be the result of multiple genetic factors.
Adult↗
Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.
A human autosomal XY sex reversal locus, SRA1, associated with the skeletal malformation syndrome campomelic dysplasia (CMPD1), has been placed at distal 17q. The SOX9 gene, a positional candidate from the chromosomal location and expression pattern reported for mouse Sox9, was isolated and characterized. SOX9 encodes a putative transcription factor structurally related to the testis-determining factor SRY and is expressed in many adult tissues, and in fetal testis and skeletal tissue. Inactivating mutations on one SOX9 allele identified in nontranslocation CMPD1-SRA1 cases point to haploinsufficiency for SOX9 as the cause for both campomelic dysplasia and autosomal XY sex reversal. The 17q breakpoints in three CMPD1 translocation cases map 50 kb or more from SOX9.
Amino Acid Sequence↗
One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjögrens' syndrome.
A cDNA library was prepared from peripheral blood lymphocytes of an autoimmune patient with primary Sjögrens' syndrome. The cDNA library was screened with the patients own autoimmune serum being monospecific for the nuclear autoantigen La/SS-B. Thereby an alternative type of La mRNA was identified that differed from the known La mRNA due to an exchange of the exon 1. Sequencing of the genomic region between the exons 1 and 2 showed that the alternative 5'-end is a part of the intron. In addition, the presence of an alternative promoter site, which exists within the intron downstream of the exon 1, became evident. In consequence, the alternative La mRNA is the result of a promoter switching combined with an alternative splicing mechanism. In the intron, further transcription factor binding sites, including a NF-kappa B element, were identified leading to the suggestion that the expression of the gene encoding for the nuclear autoantigen La/SS-B alters in dependence on disease conditions.
Alternative Splicing↗
A human keratin 14 "knockout": the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein.
Since their discovery, the function of intermediate filaments (IFs) has remained obscure. In skin, epidermal cells have extensive cytoskeletal architectures of IFs, composed of type I and type II keratin heterodimers. Clues to possible functions of these proteins have come from recent studies showing that several autosomal-dominant, blistering skin disorders are caused by defects in genes that encode epidermal keratins. These diseases all exhibit cell degeneration and keratin network perturbations in cells that express the particular mutant keratin gene. However, it is not clear from these studies whether cytolysis arises from the presence of large insoluble keratin aggregates that compromise cellular physiology or from the absence of an extensive keratin filament network, which jeopardizes mechanical integrity. We report here the analysis of an extremely rare case of severe recessive epidermolysis bullosa simplex (EBS), where the patient lacks a discernible keratin filament network in basal epidermal cells. Genetic analyses revealed a homozygous point mutation that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of K14. The consanguineous parents were normal, each harboring one copy of the null K14 mutation. Analysis of cultured keratinocytes enabled us to document that the loss of K14 is not compensated for by the up-regulation of any other type I keratin. When taken together with the in vivo studies showing the presence of cell fragility generated from the lack of an extensive basal keratin network, these findings provide the first clear demonstration of loss of function associated with the absence of an IF protein in vivo.
Amino Acid Sequence↗
Developmental expression of human cartilage matrix protein.
Cartilage matrix protein (CMP) is a non-collagenous component of cartilage with a yet unknown function. In this study we used in situ hybridization to investigate the temporal and spatial distribution of CMP transcripts during human embryonic and early fetal development, and compared it to the pattern of expression observed for collagen types I, II, X, and decorin. The distribution of CMP and collagen type II transcripts followed a similar pattern in the embryonic bone anlage, the fetal growth plate, and the developing vertebral column. Expression was highest in the upper hypertrophic and lower proliferative zone, whereas calcified cartilage was negative throughout the different stages of bone development. Chondrocytes of calcified cartilage, however, were not quiescent but expressed collagen type X. The onset of collagen type X expression was linked to hypertrophy and occurred before calcification became apparent. In contrast, decorin and collagen type I were highly expressed in bone and perichondrium but not in growth plate cartilage. During the development of the synovial joints a different pattern of expression emerged. After formation of the joint cavity, there was a halt in expression of CMP but not of collagen type II in chondrocytes close to the articular surface. A band of CMP negative chondrocytes covering the joint surface was observed in all joints investigated. Decorin mRNA was demonstrated in the reserve zone adjacent to the joints, but not in articular cartilage. Extraskeletal expression of CMP was observed in the embryonic retina. The results demonstrate the differential expression of CMP during human skeletal development and chondrocyte differentiation. The distribution of CMP transcripts is unique and distinct from other known matrix genes.
Bone and Bones↗
Autosomal dominant spondylarthropathy due to a type II procollagen gene (COL2A1) point mutation.
Osteoarthrosis represents a very common disease with heterogeneous etiology. In some pedigrees linkage of the condition with the type II collagen gene (COL2A1) has been established, but information on the underlying gene defect is still incomplete as only one mutation causing this phenotype has been identified. We analyzed the COL2A1 gene in a 27-year-old woman and her 47-year-old mother presenting with severe premature osteoarthrosis and X-ray signs compatible with mild spondyloepiphyseal dysplasia. Examination of the complete gene in both patients was done by amplification of all 54 exons, screening of the PCR products by SSCP-analysis, and subsequent sequencing. In mother and daughter a G to A transition at the 5'-end of exon 21 was detected, leading to a substitution of serine for glycine at position 274 of the triple helical domain. The mutation was not present in unaffected family members or in healthy control individuals. The autosomal dominant spondylarthropathies may represent the less severe entities of the clinical spectrum of type II collagenopathies.
Adult↗
WT1 mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion.
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Amino Acid Sequence↗
Ehlers-Danlos syndrome type VII: phenotype and genotype.
A patient suffering from a severe form of Ehlers-Danlos syndrome is presented (EDS type VII). The presence of bilateral congenital hip dislocation, generalized joint hypermobility and a soft hyperelastic skin with abnormal scarring suggested a specific collagen type I defect. SDS-PAGE analysis of collagens secreted into the medium of fibroblast cultures showed a retarded migration of more than half of the alpha 2(I) chains. CNBr peptide mapping of the HPLC-purified altered chain localized the mutant locus to the N-terminal region of the protein. cDNA analysis of the corresponding gene COL1A2 revealed, in addition to the expected collagen sequence, a transcript missing the entire exon 6. This exon encodes a major crosslinking site within collagen fibres as well as the N-propeptidase cleavage site. The skipping of exon 6 is caused by a splice site mutation substituting an A for a G at the first nucleotide of intron 6.
Base Sequence↗
The type II collagenopathies: a spectrum of chondrodysplasias.
With the application of molecular techniques the aetiopathogenesis of skeletal dysplasias is gradually elucidated. Recent advances show that some bone dysplasias result from defects in the biosynthesis of type II (cartilage) collagen. Clinical entities caused by mutations in the COL2A1 gene coding for type II collagen comprise achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler arthroophthalmopathy and mild dominant spondyloarthropathy. The mutations are expressed in the heterozygous state, and inheritance of type II collagenopathies is autosomal dominant. The wide range of clinical manifestations is not well understood but characterization of the basic defect may provide clues to establish specific genotype-phenotype correlations.
Collagen Diseases↗
Kniest dysplasia is caused by dominant collagen II (COL2A1) mutations: parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia.
We describe two unrelated children with Kniest dysplasia, a severe autosomal dominant form of chondrodysplastic dwarfism associated with cleft palate, progressive arthropathy, myopia and retinal detachment. In the first patient the disorder was caused by a 28 base pair exon 12/intron 12 deletion in the gene coding for type II collagen. Her mother had mild abnormalities of the vertebral bodies and long bones compatible with abnormalities seen in Stickler arthro-ophthalmopathy. The second child had a transition of AG to GG at the 3' splice site of intron 20 of the COL2A1 gene. Her father had premature polvarthrosis interpreted as a sequela of mild spondyloepiphyseal dysplasia. Molecular studies revealed that the mother of the first and the father of the second child each had somatic mosaicism of the same mutation as their children. Heterozygous mutations of the gene coding for type II collagen can cause Kniest dysplasia, and somatic mosaicism for the same mutations can result in the Stickler phenotype or in mild spondyloepiphyseal dysplasia leading to premature polyarthrosis.
Adult↗