Evidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis.

Available evidences suggest that podoconiosis is triggered by long term exposure of bare feet to volcanic red clay soil particles. Previous genome-wide studies in Ethiopia showed association between the HLA class II region and disease susceptibility. However, functional relationships between the soil trigger, immunogenetic risk factors and the immunological basis of the disease are uncharted.

Clinical, hematological, biochemical, and histopathological evaluations in domestic cats (Felis catus) infected by Leishmania infantum.

A high frequency of feline leishmaniasis has been reported in several countries. However, much information about disease progression in cats still needs to be clarified. This study aimed to verify the occurrence of clinicopathological changes in cats infected with Leishmania infantum.

Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis.

Background: Podoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease.

Infection of Lutzomyia longipalpis in cats infected with Leishmania infantum.

The clinical manifestations most frequently observed in cats with leishmaniasis caused by Leishmania infantum are cutaneous alterations, which suggest a high parasitic load in the skin and the possibility of infecting a vector. This study evaluated the infectiousness of to phlebotomine sand flies cats infected with L. infantum.

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing.

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations.

SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation.

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway.

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.

The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.

Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported.

Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum".

Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.

Congenital microcephaly.

The underlying etiologies of genetic congenital microcephaly are complex and multifactorial. Recently, with the exponential growth in the identification and characterization of novel genetic causes of congenital microcephaly, there has been a consolidation and emergence of certain themes concerning underlying pathomechanisms. These include abnormal mitotic microtubule spindle structure, numerical and structural abnormalities of the centrosome, altered cilia function, impaired DNA repair, DNA Damage Response signaling and DNA replication, along with attenuated cell cycle checkpoint proficiency.

Mutations in PIK3R1 cause SHORT syndrome.

SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.

Microcephaly-capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways.

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.

Understanding the impact of 1q21.1 copy number variant.

Background: 1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate.

CUL4B-deficiency in humans: understanding the clinical consequences of impaired Cullin 4-RING E3 ubiquitin ligase function.

Cullin's encode the structural components for one of the most abundant E3 ubiquitin ligase families in eukaryotes accounting for as many as 400 distinct E3 ubiquitin ligases. Because of their modular assembly involving combinations of multiple distinct adaptor and substrate receptor proteins, it comes as no surprise that these E3's are implicated in a plethora of fundamental biochemical processes ranging from DNA replication and repair to transcription and development. Herein, we focus on one member of the cullin family, namely the Cullin 4-RING E3 ligases (CRL4's).