Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes.

ABSTRACT: Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh^-/- ), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh^-/- mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (S_XL ), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh^-/- mouse is a valuable model for future studies of human CIII deficiency.

SUBMITTER: Vidali S

PROVIDER: S-EPMC8649870 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A homozygous deletion of exon 1 in WISP3 causes progressive pseudorheumatoid dysplasia in two siblings.

Project description:Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive disease that causes progressive joint stiffness and pain. It is associated with loss-of-function mutations in the WISP3 gene. We describe two sisters suffering from PPD in whom molecular genetic analysis revealed a homozygous deletion of exon 1 and of the 5'UTR of the WISP3 gene. This is the first time that a gross deletion has been described as the causal mutation in PPD.

| S-EPMC4785582 | biostudies-other

GM2 Activator Deficiency Caused by a Homozygous Exon 2 Deletion in GM2A.

Project description:GM2 activator (GM2A) deficiency (OMIM 613109) is a rare lysosomal storage disorder, with onset typically in infancy or early childhood. Clinically, it is almost indistinguishable from Tay-Sachs disease (OMIM 272800) or Sandhoff disease (OMIM 268800); however, traditionally available biochemical screening tests will most likely reveal normal results. We report a 2-year-old male with initially normal development until the age of 9 months, when he presented with developmental delay and regression. Workup at that time was unrevealing; at 15 months, he had abnormal brain MRI findings and a cherry red spot on ophthalmological examination. Family history and all laboratory studies were uninformative. The combination of a cherry red spot and developmental regression was strongly suggestive of a lysosomal storage disorder. Sequence analysis of GM2A did not reveal any pathogenic variants; however, exon 2 of GM2A could not be amplified by PCR, raising suspicion for a large, homozygous deletion. Subsequent copy number analysis confirmed a homozygous deletion of exon 2 in GM2A. This is the first reported case of GM2A deficiency being caused by a whole exon deletion. We describe previously unreported electron microscopy findings in this disease, thus expanding the clinical and variant spectrum for GM2 activator deficiency. These findings demonstrate the increased degree of suspicion required for diagnosis of this rare disorder. Brief Summary: This case of GM2 activator deficiency was caused by a homozygous deletion in GM2A, demonstrating the need to include exon level copy number analysis in any workup to fully exclude this disorder.

| S-EPMC5874204 | biostudies-literature

15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes.

Project description:The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder and schizophrenia, though the clinical profile varies considerably. Two mouse models of this syndrome, with hemizygous deletion of the orthologous region in the murine genome, have recently been shown to recapitulate a number of the behavioral and physiological deficits that characterize the human condition. Still, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral and physiological deficits in mice than the 15q13.3 hemizygous deletion. Here we report the characterization of a 15q13.3 knockout mouse. We observed marked deficits including altered seizure susceptibility, autistic behavior-related phenotypes, and auditory sensory processing. Several of these deficits, albeit less pronounced, were also found in the 15q13.3 hemizygous littermates indicating a gene-dosage dependency. Our findings strongly indicate that studies of the hemi- and homozygous 15q13.3 mouse strains will facilitate understanding of the biological mechanisms of severe mental disorders.

| S-EPMC5545711 | biostudies-literature

A human laterality disorder associated with a homozygous WDR16 deletion.

Project description:The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

| S-EPMC4538206 | biostudies-literature

Two Siblings Homozygous for F508del-CFTR Have Varied Disease Phenotypes and Protein Biomarkers.

Project description:Two siblings with CF are homozygous for F508del (referred to as Subject A and Subject B). Despite having the same CFTR genotype and similar environment, these two subjects exhibited different disease phenotypes. We analyzed their medical records and CF Foundation Registry data and measured inflammatory protein mediators in their sputum samples. Then, we examined the longitudinal relationships between inflammatory markers and disease severity for each subject and compared between them. Subject A presented a more severe disease than Subject B. During the study period, Subject A had two pulmonary exacerbations (PEs) whereas Subject B had one mild PE. The forced expiratory volume in 1 s (FEV1, % predicted) values for Subject A were between 34-45% whereas for Subject B varied between 48-90%. Inflammatory protein mediators associated with neutrophils, Th1, Th2, and Th17 responses were elevated in sputum of Subject A compared with Subject B, and also in samples collected prior to and during PEs for both subjects. Neutrophilic elastase (NE) seemed to be the most informative biomarkers. The infectious burden between these two subjects was different.

| S-EPMC7961721 | biostudies-literature

Detection of internal exon deletion with exon Del.

Project description:BackgroundExome sequencing allows researchers to study the human genome in unprecedented detail. Among the many types of variants detectable through exome sequencing, one of the most over looked types of mutation is internal deletion of exons. Internal exon deletions are the absence of consecutive exons in a gene. Such deletions have potentially significant biological meaning, and they are often too short to be considered copy number variation. Therefore, to the need for efficient detection of such deletions using exome sequencing data exists.ResultsWe present ExonDel, a tool specially designed to detect homozygous exon deletions efficiently. We tested ExonDel on exome sequencing data generated from 16 breast cancer cell lines and identified both novel and known IEDs. Subsequently, we verified our findings using RNAseq and PCR technologies. Further comparisons with multiple sequencing-based CNV tools showed that ExonDel is capable of detecting unique IEDs not found by other CNV tools.ConclusionsExonDel is an efficient way to screen for novel and known IEDs using exome sequencing data. ExonDel and its source code can be downloaded freely at https://github.com/slzhao/ExonDel.

| S-EPMC4288651 | biostudies-literature

Characterising heart rhythm abnormalities associated with Xp22.31 deletion.

Project description:BackgroundGenetic deletions at Xp22.31 are associated with the skin condition X linked ichthyosis (XLI), and with a substantially increased risk of atrial fibrillation/flutter (AF), in males. AF is associated with elevated thrombosis, heart failure, stroke and dementia risk.MethodsThrough: (a) examining deletion carriers with a diagnosis of AF in UK Biobank, (b) undertaking an online survey regarding abnormal heart rhythms (AHRs) in men/boys with XLI and female carriers of XLI-associated deletions and (c) screening for association between common genetic variants within Xp22.31 and idiopathic AF-related conditions in UK Biobank, we have investigated how AHRs manifest in deletion carriers, and have identified associated risk factors/comorbidities and candidate gene(s). Finally, we examined attitudes towards heart screening in deletion carriers.ResultsWe show that AHRs may affect up to 35% of deletion carriers (compared with <20% of age-matched non-carriers), show no consistent pattern of onset but may be precipitated by stress, and typically resolve quickly and respond well to intervention. Gastrointestinal (GI) conditions and asthma/anaemia were the most strongly associated comorbidities in male and female deletion carriers with AHR, respectively. Genetic analysis indicated significant enrichment of common AF risk variants around STS (7 065 298-7 272 682 bp in GRCh37/hg19 genome build) in males, and of common GI disorder and asthma/anaemia risk variants around PNPLA4 (7 866 804-7 895 780 bp) in males and females, respectively. Deletion carriers were overwhelmingly in favour of cardiac screening implementation.ConclusionOur data suggest AHRs are frequently associated with Xp22.31 deletion, and highlight subgroups of deletion carriers that may be prioritised for screening. Examining cardiac function further in deletion carriers, and in model systems lacking steroid sulfatase, may clarify AF pathophysiology.

| S-EPMC10359567 | biostudies-literature

Characterization of a Knock-In Mouse Model with a Huntingtin Exon 1 Deletion.

Project description:BackgroundThe Huntingtin (HTT) N-terminal domains encoded by Huntingtin's (HTT) exon 1 consist of an N17 domain, the polyglutamine (polyQ) stretch and a proline-rich region (PRR). These domains are conserved in mammals and have been hypothesized to modulate HTT's functions in the developing and adult CNS, including DNA damage repair and autophagy.ObjectiveThis study longitudinally characterizes the in vivo consequences of deleting the murine Htt N-terminal domains encoded by Htt exon 1.MethodsKnock-in mice with a deletion of Htt exon 1 sequences (HttΔE1) were generated and bred into the C57BL/6J congenic genetic background. Their behavior, DNA damage response, basal autophagy, and glutamatergic synapse numbers were evaluated.ResultsProgeny from HttΔE1/+ intercrosses are born at the expected Mendelian frequency but with a distorted male to female ratio in both the HttΔE1/ΔE1 and Htt+/+ offspring. HttΔE1/ΔE1 adults exhibit a modest deficit in accelerating rotarod performance, and an earlier increase in cortical and striatal DNA damage with elevated neuronal pan-nuclear 53bp1 levels compared to Htt+/+ mice. However, a normal response to induced DNA damage, normal levels of basal autophagy markers, and no significant differences in corticocortical, corticostriatal, thalamocortical, or thalamostriatal synapses numbers were observed compared to controls.ConclusionOur results suggest that deletion of the Htt N-terminus encoded by the Htt exon 1 does not affect Htt's critical role during embryogenesis, but instead, may have a modest effect on certain motor tasks, basal levels of DNA damage in the brain, and Htt function in the testis.

| S-EPMC8595774 | biostudies-literature

Delineation of 2q32q35 deletion phenotypes: two apparent "proximal" and "distal" syndromes.

Project description:We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1-q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6?Mb deletion in patients 1 and 2 and a 24.7?Mb deletion in patient 3. We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2, and CPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene.

| S-EPMC3690635 | biostudies-literature

Comparing three phenotypes: Comparing molecular assessment of implantation biopsy

Project description: Not available

| S-DIXA-D-1127 | biostudies-other