Phenotype matters

Biesecker, Leslie G.

doi:10.1038/ng0404-323

Cited by 16 publications

(11 citation statements)

References 5 publications

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“…The skeletal disorders caused by mutations in FLNB are very similar to those caused by mutations in FLNA (9). Interestingly, FLNA and FLNB are coexpressed within chondrocytes (7) and physically interact with each other in neurons (10), suggesting that FLNA and FLNB may form both homodimers and heterodimers.…”

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confidence: 72%

Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development

Zhou

Tian²,

Sandzén³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

100

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Mutations in filamin B (FLNB), a gene encoding a cytoplasmic actin-binding protein, have been found in human skeletal disorders, including boomerang dysplasia, spondylocarpotarsal syndrome, Larsen syndrome, and atelosteogenesis phenotypes I and III. To examine the role of FLNB in vivo, we generated mice with a targeted disruption of Flnb. Fewer than 3% of homozygous embryos reached term, indicating that Flnb is important in embryonic development. Heterozygous mutant mice were indistinguishable from their wild-type siblings. Flnb was ubiquitously expressed; strong expression was found in endothelial cells and chondrocytes. Flnb-deficient fibroblasts exhibited more disorganized formation of actin filaments and reduced ability to migrate compared with wild-type controls. Flnb-deficient embryos exhibited impaired development of the microvasculature and skeletal system. The few Flnb-deficient mice that were born were very small and had severe skeletal malformations, including scoliotic and kyphotic spines, lack of intervertebral discs, fusion of vertebral bodies, and reduced hyaline matrix in extremities, thorax, and vertebrae. These mice died or had to be euthanized before 4 weeks of age. Thus, the phenotypes of Flnb-deficient mice closely resemble those of human skeletal disorders with mutations in FLNB.chondrocytes ͉ endothelial cell ͉ gene targeting F ilamins are large actin-binding proteins that stabilize the actin cytoskeleton, link the actin network with cellular membranes, and mediate interactions between actin and transmembrane receptors (1). In mouse, there are three filamin genes, Flna, Flnb, and Flnc. Flna and Flnb, which encode large proteins with 70% structural similarity, are ubiquitously expressed, whereas Flnc, encoding a much smaller protein, is expressed in heart and skeletal muscles. It has been proposed that filamins are important for fetal development by regulating the communication between extracellular signals and the cellular cytoskeleton to guide migration of cells into appropriate anatomical sites (1). In addition to actin, filamins are capable of binding to a wide range of molecules involved in cellular signaling and transcriptional regulation (2, 3).FLNB was first isolated as a protein that interacts with the cytoplasmic tail of glycoprotein Ib␣ (4, 5). The 2,603-aa chain of FLNB contains an amino-terminal actin-binding domain and a backbone of 24 Ig-like rod domain repeats disrupted by two hinge regions (6). Mouse Flnb is located on chromosome 14 and consists of 47 exons. In mouse embryos, Flnb is expressed in vertebral bodies, and it has been suggested that Flnb may play a role in vertebral segmentation, joint formation, and endochondral ossification (7).Mutations in the human FLNB gene have been found in several skeletal disorders, including spondylocarpotarsal syndrome, autosomal-dominant Larsen syndrome, atelosteogenesis I and III (7), and boomerang dysplasia (8). The skeletal disorders caused by mutations in FLNB are very similar to those caused by mutations in FLNA (9). Interesting...

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mentioning

confidence: 72%

Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development

Zhou

Tian²,

Sandzén³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

100

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“…Although many of the reasons for heterogeneity are very difficult to control in practice, we recommend the founding or extending of disease or disorder-specific data registries (see Biesecker, 2004) as a public resource for the research community, to provide help and establish unified guidelines for controlling heterogeneity. This effort needs to be specific to each disease or disorder, as phenotype definition is a completely different issue in, for example, common cancers (clear phenotype) than in psychiatric disorders (unclear phenotype).…”

Section: Use Of Human Datamentioning

confidence: 99%

Replication in genetic studies of complex traits

Sillanpää

Auranen

2004

Annals of Human Genetics

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SummaryDisappointments in replicating initial findings in gene mapping for complex traits are often attributed to small sample sizes and inadequate techniques to determine the threshold value. This is clearly not the whole truth. More fundamental reasons lie in the inherent heterogeneity related to disease, including genetic heterogeneity, differences in allele frequencies, and context-dependency in genetic architecture. There are also other reasons related to the data collection and analysis. Replication may remain a source of frustration unless more emphasis is put on controlling these sources of heterogeneity between studies.

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“…The description of phenotypic variation has become a central topic for translational research and genomic medicine (4–7), and ‘computable’ descriptions of human disease using HPO phenotypic profiles (also known as ‘annotations’) have become a key element in a number of algorithms being used to support genomic discovery and diagnostics. Here, we describe the latest improvements to the tools and resources being developed by the HPO Consortium and the Monarch Initiative, and provide an overview of external tools and databases that are using the HPO for translational research and diagnostic decision support.…”

Section: Introductionmentioning

confidence: 99%

The Human Phenotype Ontology in 2017

et al. 2016

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Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

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Phenotype matters

Cited by 16 publications

References 5 publications

Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development

Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development

Replication in genetic studies of complex traits

The Human Phenotype Ontology in 2017

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