Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer\u27s disease

The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of beta-amyloid, the key process in Alzheimer\u27s disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the gamma-cleavage activities of PSENs that produce Abeta, but not the epsilon-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 auto-cleavage was more resistant to the mutation remodeling than the epsilon-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP epsilon- and Notch S3- cleavage activities, but G382A inhibits APP gamma-cleavage and Abeta production and a P433A elevates Abeta. The G382A variant cannot restore the normal cellular ER Ca(2+) leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca(2+) leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions

Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies

Tumors of the jaws may represent different human disorders and frequently associate with pathologic bone fractures. In this report, we analyzed two affected siblings from a family of Russian origin, with a history of dental tumors of the jaws, in correspondence to original clinical diagnosis of cementoma consistent with gigantiform cementoma (GC, OMIM: 137575). Whole exome sequencing revealed the heterozygous missense mutation c.1067G \u3e A (p.Cys356Tyr) in ANO5 gene in these patients. To date, autosomal-dominant mutations have been described in the ANO5 gene for gnathodiaphyseal dysplasia (GDD, OMIM: 166260), and multiple recessive mutations have been described in the gene for muscle dystrophies (OMIM: 613319, 611307); the same amino acid (Cys) at the position 356 is mutated in GDD. These genetic data and similar clinical phenotypes demonstrate that the GC and GDD likely represent the same type of bone pathology. Our data illustrate the significance of mutations in single amino-acid position for particular bone tissue pathology. Modifying role of genetic variations in another gene on the severity of the monogenic trait pathology is also suggested. Finally, we propose the model explaining the tissue-specific manifestation of clinically distant bone and muscle diseases linked to mutations in one gene

Age- and genotype-related neurophysiologic reactivity to oxidative stress in healthy adults

The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer\u27s and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28-50) and older (age range 51-82) cohorts and stratified by ApoE genotype. The younger ApoE-epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease

Prenatal diagnosis of Prader‐Willi syndrome due to uniparental disomy with NIPS: Case report and literature review

Abstract Background PWS is challenging to diagnose prenatally due to a lack of precise and well‐characterized fetal phenotypes and noninvasive markers. Here we present the case of prenatal diagnosis of Prader‐Willi syndrome, which was suspected with whole‐genome NIPS. Methods Whole‐genome noninvasive prenatal screening showed a high risk for trisomy 15. Amniocentesis followed by FISH analysis and SNP‐based chromosomal microarray was performed. Results Simultaneous analysis of maternal and fetal samples with SNP microarrays demonstrated maternal uniparental disomy (UPD). Conclusion The presented case is the first case of PWS described in detail, which was suspected by NIPS results. It demonstrates that the choice of confirmation methods concerning the time needed is crucial for the right diagnosis. We suppose that prenatal testing of UPD is essential for chromosome regions, which play a key role in the appearance of various gene‐imprinting failure syndromes like PWS or AS

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders