Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the gene, required for mitochondrial fragmentation. dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein we report on the case of a boy affected by epileptic encephalopathy carrying two heterozygous variants () of the gene: a pathogenic variant (PV) c.1085G>A (p.Gly362Asp) accompanied with a variant of unknown significance (VUS) c.1535T>C (p.Ile512Thr). Amplicon sequencing of the mother's DNA revealed the presence of the PV and VUS in 5% of cells, with the remaining cells presenting only VUS. Functional investigations performed on the patient and his mother's cells unveiled altered mitochondrial respiratory chain activities, network architecture and Ca homeostasis as compared with healthy unrelated subjects' samples. Modelling Drp1 harbouring the two variants, separately or in combination, resulted in structural changes as compared with Wt protein. Considering the clinical history of the mother, PV transmission by a maternal germline mosaicism mechanism is proposed. Altered Drp1 function leads to changes in the mitochondrial structure and bioenergetics as well as in Ca homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467311 | PMC |
| http://dx.doi.org/10.3390/genes12091295 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Family Genetic Risk Communication and Reverse Cascade Testing in the BabySeq Project.
Genet Med
December 2024
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
Purpose: Genomic sequencing of newborns (NBSeq) can initiate disease surveillance and therapy for children, and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and had a risk for autosomal dominant disease identified.
Methods: We conducted semi-structured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely-pathogenic (P/LP) variant associated with an autosomal dominant (AD) childhood- and/or adult-onset disease returned.
Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.
Genet Med
December 2024
Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:
Objectives: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modelling the natural history, and uncovering genotype-phenotype associations.
Methods: A cross-sectional analysis of 90 published and one novel case was performed, employing a Human Phenotype Ontology-based approach.
From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.
Eur J Neurol
January 2025
Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Purpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.
Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.
Variant Spectrum of Renal Ciliopathies in Turkish Cohort and Genotype-Phenotype Association Specifically in Autosomal Dominant Polycystic Kidney Disease.
Clin Genet
December 2024
Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey.
Renal ciliopathies are a genetically and phenotypically heterogeneous group of diseases characterized by cystic and dysplastic kidneys. The aim of this study was to investigate the correlation between genetic changes that cause renal ciliopathies and phenotypic outcomes. The study group consisted of 137 patients diagnosed with renal ciliopathy disease.
View Article and Find Full Text PDFFamilial hypercholesterolemia in Chinese children and adolescents: a multicenter study.
Lipids Health Dis
December 2024
Department of Endocrinology, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China.
Background: Familial hypercholesterolemia (FH) is an inherited disorder mainly marked by increased low-density lipoprotein cholesterol (LDL-C) concentrations and a heightened risk of early-onset arteriosclerotic cardiovascular disease (ASCVD). This study seeks to characterize the genetic spectrum and genotype‒phenotype correlations of FH in Chinese pediatric individuals.
Methods: Data were gathered from individuals diagnosed with FH either clinically or genetically at multiple hospitals across mainland China from January 2016 to June 2024.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!