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Background: Consanguineous marriage is a major contributing factor for many genetic diseases and a burden to the healthcare system and national economy due to costly long-term care. Earlier studies highlighted the significantly limited awareness of the higher prevalence of genetic disease due to consanguinity even among the educated Arabs. In Saudi Arabia, more than 50% of marriages are between first cousins. This national study aims to gauge the level of the public awareness regarding the consanguinity and its impact on prevalence of genetic diseases across the Saudi Arabia. Methods: A cross-sectional bilingual online survey was conducted across Saudi Arabia, distributed through a variety of social media platforms for all residents. Pooled summary data was used from the participants. Results: Majority of the 9191 participants are < 30 years of age (72.85%), single (61.35%), women (74.12%) and college educated (77.16%). Consanguineous marriages are common in the extended family of 61.24% of participants. Though majority of them (85.45%) recognise the higher genetic disease risk associated with consanguinity, low awareness among men was observed (76.61 vs 88.53%). Sickle cell anaemia and thalassemia were not considered as genetic diseases by 60.68% of males and 48.39% of females, though they are the most common genetic diseases in Saudi Arabia. More women are aware of the carrier screening tests than men (42.62 vs 34.56%). Only 6.87% know the rationale behind the national mandatory premarital screening tests and the diseases screened. Although almost all (99.18%) are active users of the social media, 47.77% of men and 57.17% of women use them to search for health-related information. Conclusion: The present study, one of the largest national surveys in highly consanguineous society, highlights that even the young and college-educated participants have low awareness of the genetic disease burden, which is strikingly high in all corners of the country. Social media platforms can be used by genetic professionals and national organizations to disseminate the reliable educational material to the public to reduce the national healthcare and economic burden in the future.

AbstractLamellar ichthyosis (LI) is a rare inherited disease where affected infants present a extensive skin scaling characterized by hyperkeratosis. Inherited mutations in the Transglutaminase 1 (TGM1) protein is one of the known causative genetic factor for the LI. The main objective of this study is to explore the impact of LI causative missense mutations on the structural and stability aspects of TGM1 protein using structural modeling, molecular docking and molecular dynamics approaches. By testing all LI causative TMG1 mutations against multiple stability prediction methods, we found that L362R and L388P mutations positioned in the Transglut_core domain were most destabilizing to the stability of TGM1 protein. These 2 mutations were 3D protein modeled and further analyzed by molecular docking and dynamic simulation methods. Molecular docking of these TGM1 mutant structures with chitosan, a natural polyphenolic compound and known inducer for transglutaminase enzyme, has shown stable molecular interactions between the native TGM1-chitosan and TGM1(L388P)-chitosan complex, when compared to the TGM1(L362R)-chitosan complex. Interestingly, molecular dynamics analysis have also yielded similar findings, where L388P-chitosan complex is shown to develop B-sheets and attain better stability, whereas TGM1-L362R complex possessed coils over the simulation period, pointing its highly destabilizing behavior on the protein structure. This study concludes that missense mutations in Transglut_core domain of the TGM1 are deleterious to the stability and structural changes of TGM1 protein and also suggest that chitosan molecule could act as a natural activator against few pathogenic TGM1 mutations. Communicated by Ramaswamy H. Sarma

AbstractThe Paget disease (PDB; OMIM is 167250) is a chronic bone disease caused by pathogenic mutations in Sequestome1/p62 (SQSTM1) gene. This study has aimed to interpret the relationship of PDB linked SQSTM1 mutations with protein structure and its molecular dynamic features. The disease causative missense mutations were initially collected, and then analyzed for their, exonic and domain distribution, impact on secondary and tertiary structures, and their ability on protein-ligand interactions, using a combination of systems biology approaches. Our results show that most PDB linked SQSTM1 missense mutations affect amino acid residues clustered within or near the UBA domain (aa 389–434), which participates in the ubiquitination of substrates. We also report that the majority mutations occurred in α-helices over β-strands but their effects on the secondary structure were mostly neutral. Global tertiary structure deviations were minimal; however, at amino acid residue level minor structural changes were evident. The molecular dynamics simulation analysis showed that both PB1 and UBA domains were under constant structural fluctuations resulting in closed form conformation of SQSMT1 protein structure, when it is bound to PRKCI ligand. We also found salt bridge conformation changes in the UBA domain of SQSTM1 mutants when they bound to the PRKCI interactor protein. This finding suggests the possibility that mutations in SQSTM1 could impair its ability to ubiquitinate the substrates, eventually affecting autophagy and apoptosis, especially in mature osteoclasts. This study presents the additional insight into structure and function relationship between SQSTM1 mutations and PDB pathogenesis. Communicated by Ramaswamy H. Sarma.

AbstractCarbonic anhydrase 2 (CA2) enzyme deficiency caused by CA2 gene mutations is an inherited disorder characterized by symptoms like osteopetrosis, renal tubular acidosis, and cerebral calcification. This study has collected the CA2 deficiency causal missense mutations and assessed their pathogenicity using diverse computational programs. The 3D protein models for all missense mutations were built, and analyzed for structural divergence, protein stability, and molecular dynamics properties. We found M-CAP as the most sensitive prediction method to measure the deleterious potential of CA2 missense mutations. Free energy dynamics of tertiary structure models of CA2 mutants with DUET, mCSM, and SDM based consensus methods predicted only 50% of the variants as destabilizing. Superimposition of native and mutant CA2 models revealed the minor structural fluctuations at the amino acid residue level but not at the whole protein structure level. Near native molecular dynamic simulation analysis indicated that CA2 causative missense variants result in residue level fluctuation pattern in the protein structure. This study expands the understanding of genotype-protein phenotype correlations underlying CA2 variant pathogenicity and presents a potential avenue for modifying the CA2 deficiency by targeting biophysical structural features of CA2 protein. Communicated by Ramaswamy H. Sarma

AbstractA large-scale DNA-based assay, namely SNaPshot, was developed and validated for the determination of allelic polymorphisms of genes associated with type II diabetes (T2D) mellitus disease in Saudi patients. The new approach is alternative to phenotyping and physiological diagnosis. The assay includes single nucleotide polymorphisms (SNPs) of seven most common genes namely, GNB-3, GCK, SLC30A, KNJ11, TCF7L2, CDKN2A/Band HNF4A.The study proved that the new genotyping assay is rapid, easy to perform and robust for screening of high risk T2D family members. The new assay can be applied in genetic testing as an important tool for identifying significant genetic factors that help in predicting diabetes at early stages of life to avoid subsequent complications. This assay can also be used to evaluate the gene risk variants in populations of other geographic origins.

Lung cancer, a major cause of death in the Western world, has a poor prognosis1. So far, therapeutic strategies have had only a limited effect. Lung cancer risk is strongly associated with cigarette smoking2,3and lung cancer pedigrees are rare. However, a possible polygenic nature of inherited predisposition to this cancer has been envisaged4–7. Mouse inbred strains with inherited predisposition and resistance to lung cancer provide an important tool for the dissection of the genetics of this complex disease7,8. The A/J strain carries the pulmonary adenoma susceptibility 1 (Pas7) locus and develops many lung tumours9. We have mapped the M. spretus-derived locus that strongly resists the lung tumorigenesis in Pas1/+ mice. This locus, pulmonary adenoma resistance 1 (Par1) maps to mouse chromosome 11, near the Rara locus, with a lod score of 5.3. In Pas1/+ mice Par1 accounts for 23% of the phenotypic variance and 10 fold reduction in total tumour volume. These results provide evidence for a major resistance locus affecting the expression of an inherited predisposition to lung cancer.