Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas

<p>Abstract</p> <p>Background</p> <p>The X-linked <it>SRPX2 </it>gene encodes a Sushi Repeat-containing Protein of unknown function and is mutated in two disorders of the Rolandic/Sylvian speech areas. Since it is linked to defects in the functioning and the development of brain areas for speech production, <it>SRPX2 </it>may thus have participated in the adaptive organization of such brain regions. To address this issue, we have examined the recent molecular evolution of the <it>SRPX2 </it>gene.</p> <p>Results</p> <p>The complete coding region was sequenced in 24 human X chromosomes from worldwide populations and in six representative nonhuman primate species. One single, fixed amino acid change (R75K) has been specifically incorporated in human SRPX2 since the human-chimpanzee split. The R75K substitution occurred in the first sushi domain of SRPX2, only three amino acid residues away from a previously reported disease-causing mutation (Y72S). Three-dimensional structural modeling of the first sushi domain revealed that Y72 and K75 are both situated in the hypervariable loop that is usually implicated in protein-protein interactions. The side-chain of residue 75 is exposed, and is located within an unusual and SRPX-specific protruding extension to the hypervariable loop. The analysis of non-synonymous/synonymous substitution rate (Ka/Ks) ratio in primates was performed in order to test for positive selection during recent evolution. Using the branch models, the Ka/Ks ratio for the human branch was significantly different (p = 0.027) from that of the other branches. In contrast, the branch-site tests did not reach significance. Genetic analysis was also performed by sequencing 9,908 kilobases (kb) of intronic <it>SRPX2 </it>sequences. Despite low nucleotide diversity, neither the HKA (Hudson-Kreitman-Aguadé) test nor the Tajima's D test reached significance.</p> <p>Conclusion</p> <p>The R75K human-specific variation occurred in an important functional loop of the first sushi domain of SRPX2, indicating that this evolutionary mutation may have functional importance; however, positive selection for R75K could not be demonstrated. Nevertheless, our data contribute to the first understanding of molecular evolution of the human <it>SPRX2 </it>gene. Further experiments are now required in order to evaluate the possible consequences of R75K on SRPX2 interactions and functioning.</p

Infantile Convulsions with Paroxysmal Dyskinesia (ICCA Syndrome) and Copy Number Variation at Human Chromosome 16p11

BACKGROUND: Benign infantile convulsions and paroxysmal dyskinesia are episodic cerebral disorders that can share common genetic bases. They can be co-inherited as one single autosomal dominant trait (ICCA syndrome); the disease ICCA gene maps at chromosome 16p12-q12. Despite intensive and conventional mutation screening, the ICCA gene remains unknown to date. The critical area displays highly complicated genomic architecture and is the site of deletions and duplications associated with various diseases. The possibility that the ICCA syndrome is related to the existence of large-scale genomic alterations was addressed in the present study. METHODOLOGY/PRINCIPAL FINDINGS: A combination of whole genome and dedicated oligonucleotide array comparative genomic hybridization coupled with quantitative polymerase chain reaction was used. Low copy number of a region corresponding to a genomic variant (Variation_7105) located at 16p11 nearby the centromere was detected with statistical significance at much higher frequency in patients from ICCA families than in ethnically matched controls. The genomic variant showed no apparent difference in size and copy number between patients and controls, making it very unlikely that the genomic alteration detected here is ICCA-specific. Furthermore, no other genomic alteration that would directly cause the ICCA syndrome in those nine families was detected in the ICCA critical area. CONCLUSIONS/SIGNIFICANCE: Our data excluded that inherited genomic deletion or duplication events directly cause the ICCA syndrome; rather, they help narrowing down the critical ICCA region dramatically and indicate that the disease ICCA genetic defect lies very close to or within Variation_7105 and hence should now be searched in the corresponding genomic area and its surrounding regions

Morphology quiz: Mediastinal adenopathy cytology from endobronchial ultrasound transbronchial aspiration (EBUS-TBNA)

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Morphology quiz: Identification of the origin of metastatic cells in pleural effusion

International audienceTest yourself in this educational case establishing the nature of the cells present in a pleural effusion of a patient with history of previous skin cancer

New human sodium/glucose cotransporter gene (KST1): identification, characterization, and mutation analysis in ICCA (infantile convulsions and choreoathetosis) and BFIC (benign familial infantile convulsions) families

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Detection of ALK and ROS1 rearrangements by immunocytochemistry on cytological samples

International audienceThe identification of ALK and ROS1 rearrangements has become essential for the theranostic management of patients with non-small cell lung cancer, especially in stage IV or inoperable patients. These testings are now performed by immunohistochemistry on histological samples and confirmed by fluorescent in situ hybridization in case of positive or doubtful results. The diagnosis of lung cancer is often performed at an advanced or metastatic stage and cytological sample could be the only material containing malignant cells available at these stages. Therefore, the detection of ALK and ROS1 rearrangement by immunocytochemical analysis on cytological specimens is needed. We performed this test on 27 cytological samples of lung adenocarcinomas, and we compared our results with several other techniques: on the same sample or on biopsy in another laboratory, on the same sample by fluorescent in situ hybridization and/or immunochemistry. We found a very good concordance between all these techniques, thus validating our immunocytochemical method on cytological samples according to the ISO 15189 norm. (C) 2018 Elsevier Masson SAS. All rights reserved

Detection of EGFR, KRAS and BRAF mutations in metastatic cells from cerebrospinal fluid

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Identification of CD146 as a novel molecular actor involved in systemic sclerosis

International audienceWe highlight for the first time that CD146/sCD146 is involved in fibrotic process during SSc. sCD146 could thus constitute a new biomarker to assess disease activity, and potentially a new target for therapeutic applications

Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR

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