Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia

2021 ◽  
Author(s):  
Sophie Sleiman ◽  
Aren E Marshall ◽  
Xiaomin Dong ◽  
Aziz Mhanni ◽  
Ismaël Alidou-D’Anjou ◽  
...  
Keyword(s):  
Early Onset ◽  
Dopamine Metabolism ◽  
Compound Heterozygous ◽  
Developmental Defects ◽  
Sibling Pairs ◽  
Molecular Etiology ◽  
Neurological Features ◽  
Compound Heterozygous Variants ◽  
Protein Variants ◽  
Ribosome Formation

Abstract SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+ Channel Gating

2018 ◽  
Vol 55 (8) ◽  
pp. 7009-7024 ◽  
Author(s):  
Paolo Ambrosino ◽  
Elena Freri ◽  
Barbara Castellotti ◽  
Maria Virginia Soldovieri ◽  
Ilaria Mosca ◽  
...  
Keyword(s):  
Early Onset ◽  
Channel Gating ◽  
K Channel ◽  
Compound Heterozygous ◽  
Additive Contribution ◽  
Compound Heterozygous Variants

scholarly journals COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sami Tabbarah ◽  
Erika Tavares ◽  
Jason Charish ◽  
Ajoy Vincent ◽  
Andrew Paterson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Retinal Degeneration ◽  
Skeletal Dysplasia ◽  
Early Onset ◽  
Protein Misfolding ◽  
Cultured Cells ◽  
Retinal Dystrophy ◽  
Compound Heterozygous ◽  
Cog Complex ◽  
Compound Heterozygous Variants

AbstractLeber congenital amaurosis (LCA), a form of autosomal recessive severe early-onset retinal degeneration, is an important cause of childhood blindness. This may be associated with systemic features or not. Here we identified COG5 compound-heterozygous variants in patients affected with a complex LCA phenotype associated with microcephaly and skeletal dysplasia. COG5 is a component of the COG complex, which facilitates retrograde Golgi trafficking; if disrupted this can result in protein misfolding. To date, variants in COG5 have been associated with a distinct congenital disorder of glycosylation (type IIi) and with a variant of Friedreich’s ataxia. We show that COG5 variants can also result in fragmentation of the Golgi apparatus and upregulation of the UPR modulator, PKR-like endoplasmic reticulum kinase (PERK). In addition, upregulation of PERK induces DNA damage in cultured cells and in murine retina. This study identifies a novel role for COG5 in maintaining ER protein homeostasis and that disruption of that role results in activation of PERK and early-onset retinal degeneration, microcephaly and skeletal dysplasia. These results also highlight the importance of the UPR pathway in early-onset retinal dystrophy and as potential therapeutic targets for patients.

scholarly journals Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease

2021 ◽  
Author(s):  
Sara N Koenig ◽  
Holly C Sucharski ◽  
Elizabeth Jose ◽  
Emma K Dudley ◽  
Francesca Madiai ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Early Onset ◽  
Null Allele ◽  
Mendelian Inheritance ◽  
Paternal Allele ◽  
Compound Heterozygous ◽  
Atherosclerotic Cardiovascular Disease ◽  
Artery Disease ◽  
Compound Heterozygous Variants

Rationale: Coronary artery disease (CAD) is a pervasive and critical healthcare problem. Elevated high density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease (ASCVD) outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving ASCVD event risk. Nevertheless, human variants in the HDL receptor, encoded by SCARB1, are associated with dyslipidemia, suggesting that HDL metabolism, not HDL-C, is a suitable target for therapy. However, variants in SCARB1 have never been directly attributed to CAD by Mendelian inheritance. Objective: To determine if compound heterozygous variants in SCARB1 cause disease in two brothers with severe, early-onset CAD. Methods and Results: Using whole exome sequencing, we have identified rare, compound heterozygous variants in SCARB1 that segregate with severe, premature CAD, following patterns of Mendelian inheritance. Using induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs) from the proband, we discovered the maternal variant (c.754_755delinsC) to be the first identified SCARB1 null allele, characterized by the absence of RNA and protein expression. Further, we demonstrate that the variant on the paternal allele (c.956G>T (p.G319V)) results in decreased cholesterol uptake, decreased SR-BI:HDL binding, and increased affinity for SR-BI dimerization. Finally, we generated a p.G319V knock-in mouse model that displays nearly 100% homozygous lethality and elevated plasma cholesterol in heterozygous animals, confirming pathogenicity of this variant. Conclusions: In summary, our data provide the first molecular mechanism to show the Mendelian inheritance of CAD as a result of human SCARB1 variants. The rarity of these variants supports pathogenicity in this family. Furthermore, SR-BI p.G319V, which has previously been reported benign in the context of heterozygosity, was uniquely presented alongside a null allele, demonstrating the disease-contributing capability of loss-of-function SCARB1 variants within the population.

scholarly journals Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS

2021 ◽  
Vol 22 (15) ◽  
pp. 7835
Author(s):  
Frederik Braun ◽  
Andreas Hentschel ◽  
Albert Sickmann ◽  
Theodore Marteau ◽  
Swantje Hertel ◽  
...  
Keyword(s):  
Molecular Pathology ◽  
Muscle Pathology ◽  
Compound Heterozygous ◽  
Proteomic Profiling ◽  
Mitochondrial Pathology ◽  
Microscopic Studies ◽  
Molecular Etiology ◽  
Relevant Compound ◽  
Mitochondrial Morphogenesis ◽  
Compound Heterozygous Variants

Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.

scholarly journals Novel Compound Heterozygous Variants in TBCD Gene Associated with Infantile Neurodegenerative Encephalopathy

Children ◽  
2021 ◽  
Vol 8 (12) ◽  
pp. 1140
Author(s):  
Chih-Ling Chen ◽  
Chien-Nan Lee ◽  
Yin-Hsiu Chien ◽  
Wuh-Liang Hwu ◽  
Tung-Ming Chang ◽  
...  
Keyword(s):  
Early Onset ◽  
Neurodegenerative Disorder ◽  
Failure To Thrive ◽  
Compound Heterozygous ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Relationship Of ◽  
Compound Heterozygotes ◽  
Insight Into

Mutations in tubulin-specific chaperon D (TBCD), the gene encoding one of the co-chaperons required for the assembly and disassembly of the α/β-tubulin heterodimers, have been reported to cause perturbed microtubule dynamics, resulting in debilitating early-onset progressive neurodegenerative disorder. Here, we identified two novel TBCD variants, c.1340C>T (p.Ala447Val), and c.817+2T>C, presented as compound heterozygotes in two affected siblings born to unaffected carrier parents. Clinical features included early-onset neurodegeneration, failure to thrive, respiratory failure, hypotonia, muscle weakness and atrophy and seizures. We established the genotype–phenotype relationship of these TBCD pathogenic variants and provided insight into the protein structural alteration that may contribute to this chaperone-associated tubulinopathy.

scholarly journals Novel FARS2 mutations in patients with non-fatal early onset encephalopathy with or without epilepsy

2020 ◽  
Author(s):  
Giulia Barcia ◽  
Marlène Rio ◽  
Zahra Assouline ◽  
Coralie Zangarelli ◽  
Charles-Joris Roux ◽  
...  
Keyword(s):  
Early Onset ◽  
Mitochondrial Diseases ◽  
Trna Synthetase ◽  
Compound Heterozygous ◽  
Mitochondrial Translation ◽  
Gene Encoding ◽  
Translation Factors ◽  
Clinical Presentations ◽  
Compound Heterozygous Variants ◽  
Spastic Tetraparesis

AbstractMitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Mutations in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations.Mutations in the FARS2 gene encoding the mitochondrial phenylalanyl-tRNA synthetase are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.

scholarly journals Exome Sequencing of 5 Families with Severe Early-Onset Periodontitis

2021 ◽  
pp. 002203452110292
Author(s):  
G.M. Richter ◽  
G. Wagner ◽  
K. Reichenmiller ◽  
I. Staufenbiel ◽  
O. Martins ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Early Onset ◽  
Alveolar Bone ◽  
Rare Variants ◽  
Stage Iv ◽  
Compound Heterozygous ◽  
Deleterious Mutations ◽  
Causal Variants ◽  
Compound Heterozygous Variants ◽  
Families With Children

Periodontitis is characterized by alveolar bone loss leading to tooth loss. A small proportion of patients develop severe periodontitis at the juvenile or adolescent age without exposure to the main risk factors of the disease. It is considered that these cases carry rare variants with large causal effects, but the specific variants are largely unknown. In this study, we performed exome sequencing of 5 families with children who developed stage IV, grade C, periodontitis between 3 and 18 y of age. In 1 family, we found compound heterozygous variants in the gene CTSC (p.R272H, p.G139R), 1 of which was previously identified in a family with prepubertal periodontitis. Subsequent targeted resequencing of the CTSC gene in 24 patients <25 y of age (stage IV, grade C) identified the known mutation p.I453V (odds ratio = 4.06, 95% CI = 1.6 to 10.3, P = 0.001), which was previously reported to increase the risk for adolescent periodontitis. An affected sibling of another family carried a homozygous deleterious mutation in the gene TUT7 (p.R560Q, CADD score >30 [Combined Annotation Dependent Depletion]), which is implicated in regulation of interleukin 6 expression. Two other affected siblings shared heterozygous deleterious mutations in the interacting genes PADI1 and FLG (both CADD = 36), which contribute to the integrity of the environment–tissue barrier interface. Additionally, we found predicted deleterious mutations in the periodontitis risk genes ABCA1, GLT6D1, and SIGLEC5. We conclude that the CTSC variants p.R272H and p.I453V have different expressivity and diagnostic relevance for prepubertal and adolescent periodontitis, respectively. We propose additional causal variants for early-onset periodontitis, which also locate within genes that carry known susceptibility variants for common forms. However, the genetic architecture of juvenile periodontitis is complex and differs among the affected siblings of the sequenced families.

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