Project description:Here we describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341.
Project description:Infantile neuroaxonal dystrophy (INAD) is an ultra-rare early-onset autosomal recessive neurodegenerative disorder due to PLA2G6 variants. Copy number analysis of SNP arrays was performed on one INAD patient sample.
Project description:An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient’s gene, it has been challenging to determine which two of the variants are responsible for the disease phenotype. To decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5’ and 3’ variants was around 19 kb at the level of genomic DNA. nCATS successfully delineated that the most 5’ and 3’ variants were located in one allele while the variant in between was in the other allele. Intriguingly, the proband’s mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study illuminates nCATS as a useful tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can tell which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.
Project description:Human data demonstrates loss of function mutations of OGFRL1 are a cause of autosomal recessive forms of cherubism. However, the gene function of OGFRL1 is unknown. We performed scRNAseq to investigate the gene function in bone marrow cells.
Project description:Human data demonstrates loss of function mutations of OGFRL1 are a cause of autosomal recessive forms of cherubism. However, the gene function of OGFRL1 is unknown. We performed scRNAseq to investigate the cell types expressing Ogfrl1 in jawbone tissue.
Project description:CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathyis) a small-vessel disease caused by loss of function mutaions of htrA1, which cleaves several extracellular matrix proteins. Here, we isolated microvessels from htra1 KO and wild type control mice to study the effect of htra1 loss of function on microvessels.
Project description:CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary cerebral small-vessel disease caused by loss of function mutations of HTRA1, which is a serine protease with a variety of targets, including extracellular matrix proteins. Htra1-KO mice accumulate matrisome proteins in cerebral blood vessels. We isolated pial arteries (the anterior cerebral artery and the middle cerebral artery) from candesartan-treated and nontreated Htra1-KO mice at 24 months of age.
Project description:Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss of function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the Cysteine 19 residue to phenylalanine or tyrosine. These individuals presented with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulated most of the skeletal anomalies observed in the affected individuals. We demonstrated that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Our findings support that heterozygous variants in MGP altering Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.
Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
