Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease

2019 ◽  
Vol 40 (8) ◽  
pp. 1084-1100 ◽  
Author(s):  
Carla Martins ◽  
Paula Frassinetti V. de Medeiros ◽  
Sandra Leistner-Segal ◽  
Larbi Dridi ◽  
Nursel Elcioglu ◽  
...  
Author(s):  
Dmitrii S. Bug ◽  
Ildar M. Barkhatov ◽  
Yana V. Gudozhnikova ◽  
Artem V. Tishkov ◽  
Natalia V. Petukhova ◽  
...  

Osteopetrosis is a group of rare inheritable disorders of the skeleton characterized by increased bone density. The disease is remarkably heterogeneous in clinical presentation and often misdiagnosed. Therefore, genetic testing and molecular pathogenicity analysis are essential for precise diagnosis and new targets for preventive pharmacotherapy. Mutations in the CLCN7 gene give rise to the complete spectrum of osteopetrosis phenotypes and are responsible for about 75% of cases of autosomal dominant osteopetrosis. In this study, we report the identification of a novel variant in the CLCN7 gene in a patient diagnosed with osteopetrosis and provide evidence for its significance (likely deleterious) based on extensive comparative genomics, protein sequence and structure analysis. A set of automated bioinformatics tools used to predict consequences of this variant identified it as deleterious or pathogenic. Structure analysis revealed that the variant is located at the same “hot spot” as the most common CLCN7 mutations causing osteopetrosis. Deep phylogenetic reconstruction showed that not only Leu614Arg, but any non-aliphatic substitutions in this position are evolutionarily intolerant, further supporting the deleterious nature of the variant. The present study provides further evidence that reconstructing a precise evolutionary history of a gene helps predicting phenotypical consequences of variants of uncertain significance.


2014 ◽  
Vol 35 (1) ◽  
pp. 129-134 ◽  
Author(s):  
Jorge Gutiérrez-Rodríguez ◽  
Elena G. Gonzalez ◽  
Íñigo Martínez-Solano

Twelve novel polymorphic microsatellite loci were isolated and characterized for the Iberian ribbed newt, Pleurodeles waltl (Caudata, Salamandridae). The distribution of this newt ranges from central and southern Iberia to northwestern Morocco. Polymorphism of these novel loci was tested in 40 individuals from two Iberian populations and compared with previously published markers. The number of alleles per locus ranged from two to eight. Observed and expected heterozygosity ranged from 0.13 to 0.57 and from 0.21 to 0.64, respectively. Cross-species amplification was tested in Pleurodeles nebulosus, which is listed as Vulnerable by the IUCN. Eight new and seven previously published loci amplified successfully in that species and thus represent a valuable conservation tool. The novel microsatellites will be useful for a better understanding of the population dynamics, demography, genetic structure, and evolutionary history of Pleurodeles waltl and P. nebulosus.


2019 ◽  
Vol 93 (24) ◽  
Author(s):  
Jeffrey B. Doty ◽  
Giorgi Maghlakelidze ◽  
Irakli Sikharulidze ◽  
Shin-Lin Tu ◽  
Clint N. Morgan ◽  
...  

ABSTRACT In 2013, a novel orthopoxvirus was detected in skin lesions of two cattle herders from the Kakheti region of Georgia (country); this virus was named Akhmeta virus. Subsequent investigation of these cases revealed that small mammals in the area had serological evidence of orthopoxvirus infections, suggesting their involvement in the maintenance of these viruses in nature. In October 2015, we began a longitudinal study assessing the natural history of orthopoxviruses in Georgia. As part of this effort, we trapped small mammals near Akhmeta (n = 176) and Gudauri (n = 110). Here, we describe the isolation and molecular characterization of Akhmeta virus from lesion material and pooled heart and lung samples collected from five wood mice (Apodemus uralensis and Apodemus flavicollis) in these two locations. The genomes of Akhmeta virus obtained from rodents group into 2 clades: one clade represented by viruses isolated from A. uralensis samples, and one clade represented by viruses isolated from A. flavicollis samples. These genomes also display several presumptive recombination events for which gene truncation and identity have been examined. IMPORTANCE Akhmeta virus is a unique Orthopoxvirus that was described in 2013 from the country of Georgia. This paper presents the first isolation of this virus from small mammal (Rodentia; Apodemus spp.) samples and the molecular characterization of those isolates. The identification of the virus in small mammals is an essential component to understanding the natural history of this virus and its transmission to human populations and could guide public health interventions in Georgia. Akhmeta virus genomes harbor evidence suggestive of recombination with a variety of other orthopoxviruses; this has implications for the evolution of orthopoxviruses, their ability to infect mammalian hosts, and their ability to adapt to novel host species.


2019 ◽  
Vol 94 (2) ◽  
pp. 366-377 ◽  
Author(s):  
Bryan M. Gee ◽  
Robert R. Reisz

AbstractNanobamus macrorhinus Schoch and Milner, 2014 is a small amphibamiform temnospondyl from the early Permian Arroyo Formation of Texas. It is most readily characterized by an elongate and partially subdivided naris. This condition is superficially reminiscent of that seen in the coeval trematopids, the group to which N. macrorhinus was originally referred to under an interpretation of the holotype as a larval form. This was discounted by later workers, but the amphibamiform affinities of the specimen were not formalized until recently. The specimen has never been described in the context of its amphibamiform affinities and remains poorly characterized, never having been sampled in a phylogenetic analysis. Here we present a complete, updated osteological description of N. macrorhinus, including an improved characterization of its unique mosaic of plesiomorphic and apomorphic features and clarification of the taxon's autapomorphies. Our analysis of the taxon's phylogenetic position within Amphibamiformes shows that N. macrorhinus was recovered as diverging after basal amphibamiforms, e.g., the micropholids, and before derived amphibamiforms, e.g., the amphibamids. This is supported by the unique mixture of retained plesiomorphies, e.g., nonforeshortened postparietals and an oval choana, and apomorphies, e.g., a narrow interorbital region and slender palatal rami of the pterygoid. These results reflect the complexity of terrestrial amphibamiform diversity and provide further insight into the evolutionary history of the lissamphibian stem in terrestrial environments.


2011 ◽  
Vol 279 (1726) ◽  
pp. 3-14 ◽  
Author(s):  
Megan L. Porter ◽  
Joseph R. Blasic ◽  
Michael J. Bok ◽  
Evan G. Cameron ◽  
Thomas Pringle ◽  
...  

Opsin proteins are essential molecules in mediating the ability of animals to detect and use light for diverse biological functions. Therefore, understanding the evolutionary history of opsins is key to understanding the evolution of light detection and photoreception in animals. As genomic data have appeared and rapidly expanded in quantity, it has become possible to analyse opsins that functionally and histologically are less well characterized, and thus to examine opsin evolution strictly from a genetic perspective. We have incorporated these new data into a large-scale, genome-based analysis of opsin evolution. We use an extensive phylogeny of currently known opsin sequence diversity as a foundation for examining the evolutionary distributions of key functional features within the opsin clade. This new analysis illustrates the lability of opsin protein-expression patterns, site-specific functionality (i.e. counterion position) and G-protein binding interactions. Further, it demonstrates the limitations of current model organisms, and highlights the need for further characterization of many of the opsin sequence groups with unknown function.


2021 ◽  
Author(s):  
Raul Buisan ◽  
Juan Moriano ◽  
Alejandro Andirko ◽  
Cedric Boeckx

Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of `archaic' haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, and especially the cerebellum and the striatum at prenatal stages, show the most divergent transcriptomic profiles when considering genes under positive selection within introgression deserts.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1786-1786
Author(s):  
Ilana Traynis ◽  
Carol D. Jones ◽  
Connie B. Gibb ◽  
Suchitra Acharya ◽  
James L. Zehnder

Abstract Combined factor V and VII deficiency is a rare bleeding disorder, with 3 cases reported in the literature. None of these cases were characterized at a molecular level. We now report a 4th case of factor V and VII deficiency, and for the first time characterize the factor V and VII mutations/polymorphisms in the proband and parents. Case history: The proband is a 5-year-old female who presented with microscopic hematuria and mild mucosal bleeding. She has 47% FV activity and 38% FVII plasma activity. Her father has a history of delayed wound healing and mild mucosal bleeding and her mother has history of mild epistaxis, menorrhagia and gingival bleeding. Results: The proband was heterozygous for a novel FV mutation, a one base deletion in exon 4 (524delG) introducing a frameshift and resulting in premature truncation of translation 33 amino acids later. In addition, she was heterozygous for 4 previously described factor VII polymorphisms: a 10-bp insertion [CCTATATCCT] at -323 in the 5′ region of the promoter, a G to A substitution in intron 1a (73 g>a), and the R353Q polymorphism in exon 8 of the F7 gene. These 3 polymorphisms have been found to be in strong allelic association in the Italian population, with mild FVII deficiency (Peyvandi et al, 1999). In addition, a R315W mutation was found in exon 8. This mutation has been reported to decrease both FVII coagulant function and factor X activation (Furlan Freguia et al, 2004). The mother was also heterozygous for FV and FVII deficiency, with FV 524 delG and FVII R315W, while as expected the father was heterozygous for the factor VII allele with the 3 associated FVII polymorphisms (Table 1). Thus the proband is heterozygous for FV deficiency and a compound heterozygote for Factor VII deficiency, inheriting FVII mutations from both parents. This is the first molecular characterization of a family with combined factor V and VII deficiency, and also the first family described with 2 different forms of combined FV and FVII deficiency within the same family. These results are consistent with this syndrome being due to chance co-inheritance of FV and FVII mutations rather than a post-translational defect as seen in combined FV and FVIII deficiency. Table 1 F5 524delG F7 R315W F7 -323 F7 IVS1 73 g>a F7 R353Q Summary of mutations/polymorphisms in a family with combined factor V and factor VII deficiency. X denotes presence of a given mutation/polymorphism in an individual. Proband X X X X X Mother X X Father X X X


2012 ◽  
Vol 26 (1) ◽  
pp. 14-26 ◽  
Author(s):  
Marianne Mathäs ◽  
Oliver Burk ◽  
Huan Qiu ◽  
Christian Nußhag ◽  
Ute Gödtel-Armbrust ◽  
...  

Abstract The xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result of whole-genome duplications. CAR genes were subsequently lost from the fish lineage, but they are conserved in all taxa of land vertebrates. This contrasts with PXR, which is found in most fish species, whereas it is lost from Sauropsida (reptiles and birds) and plays a role unrelated to xenosensing in Xenopus. This role is fulfilled in Xenopus by CAR, which exhibits low basal activity and pronounced responsiveness to activators such as drugs and steroids, altogether resembling mammalian PXR. The constitutive activity typical for mammalian CAR emerged first in Sauropsida, and it is thus common to all fully terrestrial land vertebrates (Amniota). The constitutive activity can be achieved by humanizing just two amino acids of the Xenopus CAR. Taken together, our results provide a comprehensive reconstruction of the evolutionary history of the NR1I subfamily of nuclear receptors. They identify CAR as the more conserved and remarkably plastic NR1I xenosensor in land vertebrates. Nonmammalian CAR should help to dissect the specific functions of PXR and CAR in the metabolism of xeno- and endobiotics in humans. Xenopus CAR is a first reported amphibian xenosensor, which opens the way to toxicogenomic and bioaugmentation studies in this critically endangered taxon of land vertebrates.


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