A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18)

Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons

A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report

Mutations in STK4 (MST1) are implicated in a form of autosomal recessive combined immunodeficiency, resulting in recurrent infections (especially Epstein-Barr virus viremia), autoimmunity, and cardiac malformations. Here we report a patient with an atypically mild presentation of this disease, initially presenting with severe T cell lymphopenia (< 500 per mm3) and intermittent neutropenia, but now surviving well on immunoglobulins and prophylactic antibacterial treatment. She harbors a unique STK4 mutation that lies further downstream than all others reported to date. Unlike other published cases, her mRNA transcript is not vulnerable to nonsense mediated decay (NMD) and yields a truncated protein that is expected to lose only the C-terminal SARAH domain. This domain is critical for autodimerization and autophosphorylation. While exhibiting significant differences from controls, this patient’s T cell proliferation defects and susceptibility to apoptosis are not as severe as reported elsewhere. Expression of PD-1 is in line with healthy controls. Similarly, the dysregulation seen in immunophenotyping is not as pronounced as in other published cases. The nature of this mutation, enabling its evasion from NMD, provides a rare glimpse into the clinical and cellular features associated with the absence of a “null” phenotype of this protein

Characterizing the morbid genome of ciliopathies

Background Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. Results We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. Conclusions Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies

A novel plasminogen mutation in a child with hereditary periodic syndrome: A case report

Abstract Introduction Plasminogen (PLG) deficiency is an ultrarare disease. The reported manifestations in literature were linked to pseudomembrane formation and mucosal surfaces inflammation. Recently, PLG, its activators and its receptors have gained more attention in inflammation regulatory processes, including the release of proinflammatory signaling molecules, and thus its role is believed to have clinical implications beyond what has been known. Case Report We present a child with recurrent fever who, although managed initially as familial Mediterranean fever, later on, developed a constellation of findings that were not explained by a classified autoinflammatory disease. Genetic testing revealed a novel homozygous PLG mutation (PLG: c.466G>A: p.D156N) and a likely benign heterozygous MEFV gene variant. We propose that the PLG mutation is responsible for the clinical manifestations, which may or may not be exacerbated by the coexistence of the MEFV variant. A relationship between the PLG pathway, inflammation, and FMF severity has been addressed recently in several studies. Conclusion This report highlights the recently recognized role of the PLG pathway in inflammatory diseases and describes a potentially new presentation of PLG pathogenesis. Further studies are needed to confirm this finding and allow for a more definitive conclusion

Calotropis procera: A double edged sword against glioblastoma, inhibiting glioblastoma cell line growth by targeting histone deacetylases (HDAC) and angiogenesis

Despite substantial investments in anti-glioblastoma (GBM) drug discovery over the last decade, progress is limited to preclinical stages, with clinical studies frequently encountering obstacles. Angiogenic and histone deacetylase inhibitors (HDACi) have shown profound results in pre-clinical studies. Investigating a multicomponent anti-cancer remedy that disrupts the tumor angiogenic blood vessels and simultaneously disrupts HDACs, while inducing minimal side effects, is critically needed. The crude extracts derived from medicinal plants serve as a renewable reservoir of anti-tumor drugs, exhibiting reduced toxicity compared to chemically synthesized formulations. Calotropis procera is a traditional medicinal plant, and its anticancer potential against many cancer cell lines has been reported, however its antiangiogenic and HDAC inhibitory action is largely unknown. The anticancer activity of methanol leaf extract of C. procera was tested in three types of human glioblastoma cell lines. Wild-type and transgenic zebrafish embryos were used to evaluate developmental toxicity and angiogenic activity. A human angiogenic antibody array was used to profile angiogenic proteins in the U251 GM cell line. A real-time reverse transcriptase polymerase chain reaction (RT PCR) assay was used to detect the differential expression of eleven HDAC genes in U251 cells treated with C. procera extract. The extract significantly reduced the proliferation of all three types of GBM cell lines and the cytotoxicity was found to be more pronounced in U251 GM cells, with an IC50 value of 2.63 ± 0.23 μg/ml, possibly by arresting the cell cycle at the G2/M transition. The extract did not exhibit toxic effects in zebrafish embryos, even at concentrations as high as 1000 μg/ml. The extract also inhibited angiogenic blood vessel formation in the transgenic zebrafish model in a dose-dependent manner. The results from the angiogenic antibody array have suggested novel angiogenesis targets that can be utilized to treat GBM. Real-time RT PCR analysis has shown that C. procrea extract caused an upregulation of HDAC5, 7, and 10, while the mRNA of HDAC1, 2, 3 and 8 (Class I HDACs), and HDAC4, 6, and 9 (Class II) were downregulated in U251 GM cells. The cytotoxicity of the C. procera extract on GBM cell lines could be due to its dual action by regulation of both tumor angiogenesis and histone deacetylases enzymes. Through this study, the C. procera leaf extract has been suggested as an effective remedy to treat GBM with minimal toxicity. In addition, various novel angiogenic and HDAC targets has been identified which could be helpful in designing better therapeutic strategies to manage glioblastoma multiforme in human patients

Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency

Abstract Background Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. Methods Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7). Results Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts. Conclusions Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals

Accredited genetic testing in the Arab Gulf region: reinventing the wheel.

Accredited genetic testing in the Arab Gulf region: reinventing the wheel