Search

Spinal Muscular Dystrophy (SMA) is one of the leading causes of death in children from heritable diseases. It is reported that the incidence of SMA is higher in the Saudi population. 4198 healthy volunteers between 18 to 25 years old were included in this study of which (54.7% males vs 45.3% females). Whole blood was spotted from finger pricks onto IsoCode StixTM and genomic DNA was isolated using one triangle from the machine. Carrier frequency and population-level data were used to estimate the prevalence of SMA in the population utilizing the life table method. Results showed the presence of one copy of the SMN1 gene in 108 samples, two copies in 4090 samples, and a carrier frequency of 2.6%. Carrier figurine was twofold in females and 27% of participants were children of first-cousin marriages. The birth incidence of SMA was estimated to be 32 per 100,000 birth and the total number of people living with SMA in KSA to be 2,265 of which 188 are type I, 1,213 are type II, and 864 are type III. The SMA carrier rate of 2.6 % in Saudi subjects is slightly higher than the reported global frequency with links to the consanguineous marriages.

The effect of short-term caloric restriction on gene expression in critically ill patients has not been studied. In this sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998), we examined gene expression patterns in peripheral white blood cells (buffy coat) associated with moderate caloric restriction (permissive underfeeding) in critically ill patients compared to standard feeding. Blood samples collected on study day 1 and 14 were subjected to total RNA extraction and gene expression using microarray analysis. We enrolled 50 patients, 25 in each group. Among 1751 tested genes, 332 genes in 12 pathways were found to be significantly upregulated or downregulated between study day 1 and 14 (global p value for the pathway ≤ 0.05). Using the heatmap, the differential expression of genes from day 1 to 14 in the permissive underfeeding group was compared to the standard feeding group. We further compared gene expression signal intensity in permissive underfeeding compared standard feeding by constructing univariate and multivariate linear regression models on individual patient data. We found differential expression of several genes with permissive underfeeding, most notably those related to metabolism, autophagy and other cellular functions, indicating that moderate differences in caloric intake trigger different cellular pathways.

Sonic Hedgehog (SHH) within the posteriorly located zone of polarizing activity is the main controller of the antero-posterior axis of limb development. The ZRS (zone of polarizing activity regulatory sequence) is a long-range limb-specific SHH enhancer. Several point mutations in the ZRS have been described in humans. These mutations cause enhanced SHH activity and ectopic anterior expression of SHH and a variable phenotype of preaxial polydactyly and triphalangeal thumb. Absent thumb or radius has not been reported with ZRS mutations. Here, we report on a family with a variable phenotype of preaxial polydactyly as well as absent thumb and radius, with kidney and cardiac defects. The family was screened for SALL1, SALL4, and TBX5 mutations, but all were normal. Finally, they were screened for ZRS mutations, which showed a novel point mutation within the ZRS, NG_009240.1: g.106954C>T (traditional nomenclature: ZRS619C>T) in the five affected members. This mutation was not previously reported in any public domain database, and was not found in our healthy and ethnically matched control individuals or unaffected family members. We hypothesize that interactions of SHH and SALL1 explain the overlapping features of the family described here and patients with Townes-Brocks syndrome.

Background Hepatitis B virus (HBV) affects millions of people worldwide. While some people are able to clear the virus following the first encounter, those who develop chronic infection manifest remarkable clinical heterogeneity that ranges from asymptomatic carrier state to cirrhosis and hepatocellular carcinoma. Despite extensive studies, little is known about genetic host factors that influence the outcome of chronic HBV infection. Thus, we conducted this study to investigate the genetic risk of developing active liver disease among chronic carriers of HBV. Methods In this study, we conducted a genome-wide association study (GWAS) on a cohort of patients with chronic HBV infection. Results One particular SNP that is 16 kb upstream of Ferredoxin 1 was found to have an association with complicated chronic HBV infection (cirrhosis and hepatocellular carcinoma) that reached GWAS significance, and was successfully validated on an independent set of samples. Conclusions This first GWAS in an Arab population further demonstrates the utility of this approach in elucidating the genetic risk of HBV infection-related complications and highlights the advantage of conducting GWAS in different ethnicities to achieve that goal.

C-reactive protein (CRP) is the most acute-phase reactant serum protein of inflammation and a strong predictor of cardiovascular disease. Its expression is associated with atherosclerotic plaque instability and the formation of immature micro-vessels. We have previously shown that CRP upregulates endothelial-derived Notch-3, a key receptor involved in vascular development, remodelling and maturation. In this study, we investigated the links between the bioactive monomeric CRP (mCRP) and Notch-3 signalling in angiogenesis. We used in vitro (cell counting, wound-healing and tubulogenesis assays) and in vivo (chorioallantoic membrane) angiogenic assays and Western blotting to study the angiogenic signalling pathways induced by mCRP and Notch-3 activator chimera protein (Notch-3/Fc). Our results showed an additive effect on angiogenesis of mCRP stimulatory effect combined with Notch-3/Fc promoting bovine aortic endothelial cell (BAEC) proliferation, migration, tube formation in MatrigelTM with up-regulation of phospho-Akt expression. The pharmacological blockade of PI3K/Akt survival pathway by LY294002 fully inhibited in vitro and in vivo angiogenesis induced by mCRP/Notch-3/Fc combination while blocking Notch signalling by gamma-secretase inhibitor (DAPT) partially inhibited mCRP/Notch-3/Fc-induced angiogenesis. Using a BAEC vascular smooth muscle cell co-culture sprouting angiogenesis assay and transmission electron microscopy, we showed that activation of both mCRP and Notch-3 signalling induced the formation of thicker sprouts which were shown later by Western blotting to be associated with an up-regulation of N-cadherin expression and a down-regulation of VE-cadherin expression. Thus, mCRP combined with Notch-3 activator promote angiogenesis through the PI3K/Akt pathway and their therapeutic combination has potential to promote and stabilize vessel formation whilst reducing the risk of haemorrhage from unstable plaques. © 2014 Elsevier Ltd.

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function.

Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is highly penetrant with marked phonotypical variability among inter- and intra-familial cases. We describe here a patient with a characteristic phenotype of familial bilateral symmetrical hypoplastic nails of the upper limbs and a small patella displaced by ultrasound. This patient has a homozygous mutation in the gene encoding LIM homeobox transcription factor 1 beta (LMX1B). Molecular DNA sequencing revealed that this is the first report in the literature linking a homozygous c.268C>T (p.Phe90Leu) mutation located within the highly conserved LIM-A domain of the LMX1B gene with presentation of NPS. Familial molecular analysis showed that both parents are heterozygous for the c.268C>T mutation. Therefore, prenatal diagnosis and genetic counselling are important considerations for family future planning.

Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel (AA/RRS) phocomelia syndrome are rare autosomal recessive inherited disorders characterized by aplastic/hypoplastic nails with ectopic dorsal palms, absence of humeri, hypoplastic ulnae, and bowed short radii with the elbow joints present, shown to result from missense mutations in WNT7A (p.Ala109Thr and p.Arg292Cys). Here, we describe three affected individuals belonging to two related Saudi Arabian families. All three have a similar phenotype characterized by pelvic dysplasia and truncated lower limbs compatible with the clinical diagnosis of AA/RRS. The upper limbs were more variable: one patient individual had complete amelia, whereas the others had variable limb malformations and all had absence of nails and the ventralization of the palms/digits. All affected individuals were homozygous for a mutation in exon 4 of WNT7A (c.610G>A) resulted in substitution of a highly conserved glycine to serine (p.Gly204Ser) within the Wnt signature motif [C-K-C-H-G-V-S-G-S-C]. This report describes a third cases/family in the literature with variable phenotype of AA/RRS and Fuhrmann syndrome. Identification of this mutation further underlines the crucial involvement of WNT7A in the limb development. This novel missense homozygous mutation (p.Gly204Ser) in the WNT7A gene is a unique mutation in the degree of loss of function in the upper limb development which ranges from mild to complete absence of both upper limbs (amelia). Moreover, all three affected individuals had genitourinary anomalies, linking WNT7A function to genitourinary development.

Whole-genome sequencing results from Caucasian, African, Chinese and Korean individuals have been studied and published to date. Here, we successfully generated, assembled and analyzed the first full genome of an Arabic individuals (32 healthy volunteers from Saudi Arabia) using Next Generation Sequencing. Alignment of the Arabic genome with H19 references revealed nearly 450,182 unique single-nucleotide polymorphisms (SNPs) out of 3.18 million total SNPs, including 10,609 non-synonymous SNPs and 174,579 Deletion or Insertion Polymorphisms (DIPs). A de novo assembly of 9,011 contigs sequences was identified and which are not represented within the current human reference genome sequence maintained at NCBI. In addition, the assembled Arab mitochondrial genome was closest to the L0a haplogroup sequence of the Datog ethnic group of Tanzania.

Introduction The V(D)J rearrangement of B and T cell lymphocytes during the recombination process, which is essential for the development of normal immune system function, depends critically on the presence of the recombination activating enzymes, RAG1 and RAG2. Mutations in RAG1 or RAG2 can lead to a spectrum of disorders, ranging from typical B-T-severe combined immunodeficiency to Omenn’s syndrome. Case presentation A two-month-old Saudi baby girl presented with fever, respiratory distress due to bronchiolitis, exfoliative erythroderma and a family history of childhood death within the first few months of life in two of her sisters who had had a similar clinical presentation to her own. Immunological work-up revealed an absence of circulating B lymphocytes, whereas various numbers of activated T lymphocytes were present in the peripheral blood and in the skin. Conclusion In this case, mutation analysis of the recombination activating genes RAG1 or RAG2 revealed a homozygous missense (c.1299G>A) mutation in the RAG1 gene. This is the first report in the literature linking a homozygous R396H mutation in the RAG1 gene with presentation of Omenn’s syndrome.