Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download

Genetic defects of collagen XI:the role of a minor cartilage collagen in chondrodysplasias, oral cleft defects and osteoarthrosis

Abstract Collagen XI is a minor component of articular cartilage collagen fibrils together with collagen IX. They are in close functional relationship with the major cartilage collagen II. Collagen XI has been suggested to play a role in regulating the diameter of collagen II fibrils. Together these collagens form a supportive framework in the extracellular matrix. Besides articular cartilage, these three collagens can also be found in the vitreous body of the eye, the intervertebral disc, the inner ear and in various tissues during embryonic development. As the major cartilage collagen, collagen II has been studied quite extensively. Several syndromes ranging from lethal to milder ones have been shown to result from collagen II gene defects. Far less is known about defects in genes coding for the minor cartilage collagens, IX and XI. By identifying mutations in the coding genes and observing the resulting phenotypes, the function and importance of these genes start to unravel. The goal of this study was to provide more information about collagen XI. As a quantatively minor cartilage component, it is a good candidate for mild disease phenotypes. Collagen XI gene mutations have been shown to cause relatively mild phenotypes, such as Stickler and Marshall syndromes and non-syndromic hearing loss. Seven families with a recessive chondrodysplasia, otospondylomegaepiphyseal dysplasia (OSMED), were analysed for mutations in COL11A2. This study showed that OSMED is typically caused by the absence of the α2(XI) chains. Sixty-two patients with isolated Robin sequence, cleft palate or micrognathia were analysed for COL11A2 gene mutations. Six unique nucleotide changes were found that are likely to associate with the phenotype. The results showed that collagen XI gene defects can play a role in the etiology of oral clefting, but are not common causes of these phenotypes. Altogether 72 unrelated osteoarthrosis (OA) patients and one family with OA were analysed for mutations in genes coding for collagens II, IX and XI. Eighteen percent of them were found to have a unique sequence variation. An association analysis of OA patients failed to reveal any common predisposing alleles in these genes

Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that of the autosomal dominant disorders—Stickler and Marshall syndromes—but can be distinguished by disproportionately short limbs, severe hearing loss, and lack of ocular involvement. In one family with OSMED, a homozygous Gly→Arg substitution has been described in COL11A2, which codes for the α2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of α2(XI) chains