Janus kinase 3 deficiency caused by a homozygous synonymous exonic mutation that creates a dominant splice site.
Ontology highlight
ABSTRACT:
SUBMITTER: Platt CD
PROVIDER: S-EPMC5466846 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
Publications
Janus kinase 3 deficiency caused by a homozygous synonymous exonic mutation that creates a dominant splice site.
Platt Craig D CD Massaad Michel J MJ Cangemi Brittney B Schmidt Birgitta B Aldhekri Hasan H Geha Raif S RS
The Journal of allergy and clinical immunology 20161210 1
Similar Datasets
Project description: Not available
| S-EPMC3563766 | biostudies-literature
Project description:BackgroundSMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice, and zebrafish. Our patient presented with delayed cord separation, failure to thrive, and sepsis. Retrospective whole-exome sequencing confirmed a homozygous splice-site mutation in SMARCD2.ObjectiveWe sought to provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells.MethodsHeparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34+ cells were then isolated, phenotyped, and assessed functionally.ResultsCirculating neutrophils appeared phenotypically immature, lacking multilobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow-derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of Staphylococcus aureus, consistent with a specific granule deficiency. Finally, patient bone marrow-derived CD34+ cells showed markedly impaired in vitro expansion and differentiation toward the neutrophil lineage. Before her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation and is well 8 years later.ConclusionsThis report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of hematopoietic stem cell transplantation for the hematopoietic features of SMARCD2 deficiency.
| S-EPMC8168953 | biostudies-literature
Project description:What proportion of coding sequence nucleotides have roles in splicing, and how strong is the selection that maintains them? Despite a large body of research into exonic splice regulatory signals, these questions have not been answered. This is because, to our knowledge, previous investigations have not explicitly disentangled the frequency of splice regulatory elements from the strength of the evolutionary constraint under which they evolve. Current data are consistent both with a scenario of weak and diffuse constraint, enveloping large swaths of sequence, as well as with well-defined pockets of strong purifying selection. In the former case, natural selection on exonic splice enhancers (ESEs) might primarily act as a slight modifier of codon usage bias. In the latter, mutations that disrupt ESEs are likely to have large fitness and, potentially, clinical effects. To distinguish between these scenarios, we used several different methods to determine the distribution of selection coefficients for new mutations within ESEs. The analyses converged to suggest that ∼15%-20% of fourfold degenerate sites are part of functional ESEs. Most of these sites are under strong evolutionary constraint. Therefore, exonic splice regulation does not simply impose a weak bias that gently nudges coding sequence evolution in a particular direction. Rather, the selection to preserve these motifs is a strong force that severely constrains the evolution of a substantial proportion of coding nucleotides. Thus synonymous mutations that disrupt ESEs should be considered as a potentially common cause of single-locus genetic disorders.
| S-EPMC6169883 | biostudies-literature
Project description:SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri-Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.
| S-EPMC10138022 | biostudies-literature
Project description:BackgroundMyotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state.Case presentationWe report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities.ConclusionsFunctional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.
| S-EPMC7579786 | biostudies-literature
Project description:BackgroundMutations in the ARV1 Homolog, Fatty Acid Homeostasis Modulator (ARV1), have recently been described in association with early infantile epileptic encephalopathy 38. Affected individuals presented with epilepsy, ataxia, profound intellectual disability, visual impairment, and central hypotonia. In S. cerevisiae, Arv1 is thought to be involved in sphingolipid metabolism and glycophosphatidylinositol (GPI)-anchor synthesis. The function of ARV1 in human cells, however, has not been elucidated.MethodsMutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level. Expression of the variants was determined by qPCR and Western blot. Expression of GPI-anchored proteins on neutrophils and fibroblasts was analyzed by FACS and immunofluorescence microscopy, respectively.ResultsHere we describe seven patients from two unrelated families with biallelic splice mutations in ARV1. The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy. The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis.ConclusionLoss of GPI-anchored proteins on our patients' cells confirms that the yeast Arv1 function of GPI-anchor synthesis is conserved in humans. Overlap between the phenotypes in our patients and those reported for other GPI-anchor disorders suggests that ARV1-deficiency is a GPI-anchor synthesis disorder.
| S-EPMC7303973 | biostudies-literature
Project description:Pre-mRNA transcripts in a variety of organisms, including plants, Drosophila and Caenorhabditis elegans, contain introns which are significantly richer in adenosine and uridine residues than their flanking exons. Previous analyses using exonic and intronic replacements between two nonequivalent 5'splice sites in the 469 nt long rbcS3A intron 1 provided the first evidence indicating that, in both tobacco and Drosophila nuclei, 5'splice site selection is strongly influenced by the position of that site relative to the AU transition point between exon and intron. To differentiate between two potential models for 5'splice site recognition, we have expressed a completely different set of intronic and exonic replacement constructs containing identical 5'splice sites upstream of beta-conglycinin intron 4 (115 nt). Mutagenesis and deletion of the upstream 5'splice site demonstrate that intronic AU-rich sequences function by promoting recognition of the most upstream 5'splice site rather than by masking the downstream 5'splice site. Sequence insertions define a role for AG-rich exonic sequences in plant pre-mRNA splicing by demonstrating that an AG-rich element is capable of promoting downstream 5'splice site recognition. We conclude that AU-rich intronic sequences, AG-rich exonic sequences and the 5'splice site itself collectively define 5'intron boundaries in dicot nuclei.
| S-EPMC146543 | biostudies-other
Project description:ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) plays a critical role by converting extracellular ATP to AMP, generating extracellular PPi, a potential inhibitor of calcification. Pathogenic variants in the ENPP1 cause generalized arterial calcification of infancy (GACI [OMIM 208000]). GACI, is an ultra-rare disease characterized by early-onset calcification of large and medium-sized arteries, leading to severe cardiovascular complications such as heart failure, pulmonary stenosis (PS), hypertension, and more. In this study, we report a novel homozygous splice-site pathogenic variant in ENPP1 (NM_006208, c.2230 + 5G > A; p.Asp701Asnfs*2) residing in C-terminal nuclease-like domain (NLD) of ENPP1 protein in a Pakistani family diagnosed with severe valvular PS and mild right ventricular hypertrophy (RVH). cDNA assays confirmed the skipping of exon 21, and the splice product underwent nonsense-mediated decay. Functional studies on fibroblasts from the patient demonstrated increased calcification and decreased enzymatic activity of ENPP1, recapitulating the hallmarks of GACI. By combining genetic analysis with the in vitro study, we substantiate that ENPP1:c.2230 + 5G > A variant is pathogenic, underscoring its role in the development of GACI.
| S-EPMC11558987 | biostudies-literature
Project description:Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 (IRF6) have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband's grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of IRF6 (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5' of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants.
| S-EPMC7465030 | biostudies-literature
Project description:Congenital CD59 deficiency is a recently described rare autosomal recessive disease associated with CD59 gene mutations that lead to deficient or dysfunctional CD59 protein on the cell surface. The disease is characterized by the early onset of chronic hemolysis, relapsing peripheral demyelinating neuropathy, and recurrent ischemic strokes. To date, there are 14 patients with 4 exon mutations reported globally. A young boy with early onset peripheral neuropathy and atypical hemolytic uremic syndrome is presented. Next-generation sequencing (NGS) identified a homozygous splice site variant in intron 1 of the CD59 gene (c.67 + 1G > T). This variant alters a consensus donor splicing site. Quantitative reverse transcription PCR showed that CD59 mRNA expression in the patient is significantly reduced to 0.017-fold compared to the controls. Flow cytometry showed the lack of CD59 protein on the surface of the patient's red blood cells. This variant is the first splice site mutation reported to be associated with congenital CD59 deficiency.
| S-EPMC9222317 | biostudies-literature