Gout is caused by deposition of monosodium urate crystals in joints when plasma uric acid levels are chronically elevated beyond the saturation threshold, mostly due to renal underexcretion of uric ...acid. Although molecular pathways of this underexcretion have been elucidated, its etiology remains mostly unknown. We demonstrate that gout can be caused by a mutation in LDHD within the putative catalytic site of the encoded d-lactate dehydrogenase, resulting in augmented blood levels of d-lactate, a stereoisomer of l-lactate, which is normally present in human blood in miniscule amounts. Consequent excessive renal secretion of d-lactate in exchange for uric acid reabsorption culminated in hyperuricemia and gout. We showed that LDHD expression is enriched in tissues with a high metabolic rate and abundant mitochondria and that d-lactate dehydrogenase resides in the mitochondria of cells overexpressing the human LDHD gene. Notably, the p.R370W mutation had no effect on protein localization. In line with the human phenotype, injection of d-lactate into naive mice resulted in hyperuricemia. Thus, hyperuricemia and gout can result from the accumulation of metabolites whose renal excretion is coupled to uric acid reabsorption.
DEGS1 variant causes neurological disorder Dolgin, Vadim; Straussberg, Rachel; Xu, Ruijuan ...
European journal of human genetics : EJHG,
11/2019, Letnik:
27, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Sphingolipidoses are monogenic lipid storage diseases caused by variants in enzymes of lipid synthesis and metabolism. We describe an autosomal recessive complex neurological disorder affecting ...consanguineous kindred. All four affected individuals, born at term following normal pregnancies, had mild to severe intellectual disability, spastic quadriplegia, scoliosis and epilepsy in most, with no dysmorphic features. Brain MRI findings were suggestive of leukodystrophy, with abnormal hyperintense signal in the periventricular perioccipital region and thinning of the body of corpus callosum. Notably, all affected individuals were asymptomatic at early infancy and developed normally until the age of 8-18 months, when deterioration ensued. Homozygosity mapping identified a single 8.7 Mb disease-associated locus on chromosome 1q41-1q42.13 between rs1511695 and rs537250 (two-point LOD score 2.1). Whole exome sequencing, validated through Sanger sequencing, identified within this locus a single disease-associated homozygous variant in DEGS1, encoding C4-dihydroceramide desaturase, an enzyme of the ceramide synthesis pathway. The missense variant, segregating within the family as expected for recessive heredity, affects an evolutionary-conserved amino acid of all isoforms of DEGS1 (c.656A>G, c.764A>G; p.(N219S), p.(N255S)) and was not found in a homozygous state in ExAC and gnomAD databases or in 300 ethnically matched individuals. Lipidomcs analysis of whole blood of affected individuals demonstrated augmented levels of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate and dihydrosphingomyelins with reduced levels of ceramide, sphingosine, sphingosine-1-phosphate and monohexosylceramides, as expected in malfunction of C4-dihydroceramide desaturase. Thus, we describe a sphingolipidosis causing a severe regressive neurological disease.
Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We report humans with Bardet-Biedl syndrome who display intellectual disability, ...retinitis pigmentosa, obesity, short stature and brachydactyly, stemming from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings, based on linkage analysis and exome sequencing studies of two remotely related large consanguineous families, are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Using immuno-fluorescence and live cell imaging in NIH/3T3 fibroblasts and SH-SY5Y neuroblastoma cell lines over-expressing SCAPER, we demonstrate that both wild type and mutant SCAPER are expressed in primary cilia and co-localize with tubulin, forming bundles of microtubules. While wild type SCAPER was rarely localized along the ciliary axoneme and basal body, the aberrant protein remained sequestered to the cilia, mostly at the ciliary tip. Notably, longer cilia were demonstrated both in human affected fibroblasts compared to controls, as well as in NIH/3T3 cells transfected with mutant versus wildtype SCAPER. As SCAPER expression is known to peak at late G1 and S phase, overlapping the timing of ciliary resorption, our data suggest a possible role of SCAPER in ciliary dynamics and disassembly, also affecting microtubule-related mitotic progression. Thus, we outline a human ciliopathy syndrome and demonstrate that it is caused by a mutation in SCAPER, affecting primary cilia.
How do aberrations in widely expressed genes lead to tissue‐selective hereditary diseases? Previous attempts to answer this question were limited to testing a few candidate mechanisms. To answer this ...question at a larger scale, we developed “Tissue Risk Assessment of Causality by Expression” (TRACE), a machine learning approach to predict genes that underlie tissue‐selective diseases and selectivity‐related features. TRACE utilized 4,744 biologically interpretable tissue‐specific gene features that were inferred from heterogeneous omics datasets. Application of TRACE to 1,031 disease genes uncovered known and novel selectivity‐related features, the most common of which was previously overlooked. Next, we created a catalog of tissue‐associated risks for 18,927 protein‐coding genes (https://netbio.bgu.ac.il/trace/). As proof‐of‐concept, we prioritized candidate disease genes identified in 48 rare‐disease patients. TRACE ranked the verified disease gene among the patient's candidate genes significantly better than gene prioritization methods that rank by gene constraint or tissue expression. Thus, tissue selectivity combined with machine learning enhances genetic and clinical understanding of hereditary diseases.
Synopsis
An interpretable machine‐learning framework predicts disease genes for tissue‐selective hereditary diseases. The framework highlights known and novel tissue‐selectivity features and enhances genetic diagnosis of rare‐disease patients.
An interpretable machine‐learning (ML) framework uses thousands of gene features to predict tissue‐associated disease genes.
ML models highlight known and novel tissue‐selectivity mechanisms.
An online catalogue of tissue‐associated risks for 18,927 protein‐coding genes in eight tissues is presented.
The framework and catalogue enhance genetic diagnosis of rare‐disease patients.
An interpretable machine‐learning framework predicts disease genes for tissue‐selective hereditary diseases. The framework highlights known and novel tissue‐selectivity features and enhances genetic diagnosis of rare‐disease patients.
•Autologous blood therapies are used for a variety of indications with increasing interest.•Blood is withdrawn, at times manipulated, and re-introduced to the patient.•Different autologous blood ...therapies have different indications and success rates.•Autologous blood products are rich in growth factors, cytokines and cells.•Mechanisms of action include induction of tissue proliferation and immunomodulation.
Autologous blood-derived products (ABP) are the focus of growing scientific interest and are investigated and used for multiple medical indications. ABPs hold promise thanks to their availability, ease of preparation, and low risk of adverse allogenic reaction, hypersensitivity, and contamination. Compositional analysis of ABPs reveals a diverse mixture of cellular components, cytokines and growth factors that play roles in healing processes such as tissue proliferation and angiogenesis, modulation of the local environment through chemotaxis and regulation of inflammation and the extracellular matrix, as well as several immunomodulatory actions. Thus, the administration of ABP induces supraphysiological levels of components necessary for orchestrating reparative efforts in currently difficult-to-treat medical conditions. In this article, we review the variety of autologous blood-derived products, their composition, current clinical uses, regulatory climate, and mechanisms of action.
Mutations in myotubularin-related protein 2 (
MTMR2
) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by ...severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation in
MTMR2
, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of
MTMR2
-related neuropathies.
Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of ...microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.
The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and ...generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1‐related disorders.
Identifying a novel POP1 homozygous variant in three cases within a family reveals a distinct phenotype of severe neurodevelopmental disorder with congenital anomalies. This discovery expands the phenotypic spectrum of POP1‐related disorders.
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features ...through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2
KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.
Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe ...thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.
PDF
