Exon 43 / Sarepta Therap - LARVOL DELTA

Identification of a Novel Genetic Mutation in Hypertrophic Cardiomyopathy (AHA 2025) - "Genetic testing identified a variant of uncertain significance in exon 7 of the FHL1 gene (c.755G>A, heterozygous), resulting in a cysteine-to-tyrosine substitution at codon 252 (p.Cys252Tyr); and exon 43 of the ANK2 gene (c.11454C>A, heterozygous), leading to a serine-to-arginine substitution at codon 3818 (p.Ser3818Arg)...Given her arrhythmia history and family background, she is scheduled for ICD placement.We identified a novel FHL1 variant in an adolescent with HCM, highlighting the evolving genetic landscape beyond core sarcomeric genes. This underscores the need for accurate phenotyping, vigilant reporting, and ongoing re-evaluation of variants to inform risk stratification, especially in pediatric populations.Take-home Messages:Detailed case reporting of novel genetic variants identified in HCM and longitudinal follow-up are key to improving genetic interpretation and guiding individualized care."

Cardiomyopathy • Cardiovascular • Fibrosis • Hemophilia • Hypertrophic Cardiomyopathy • Immunology • Mood Disorders • Non-obstructive Hypertrophic Cardiomyopathy • Psychiatry • Pulmonary Disease • Ventricular Tachycardia • ANK2

Eliosin-an alternative product from the HmPKD1 locus is a component of endoplasmic reticulum mitochondria membrane contact sites. (PubMed, PLoS One) - "This PKD1 locus region in human adult kidney cDNA probed by several sets of primers and sequencing produces an alternative transcript with a transcriptional start site in intron 40 that undergoes exon 42 skipping but aligns with exon 43-46 conventional splicing of the HmPKD1 gene...Strikingly, exogenous Eliosin in immortalized ADPKD renal epithelial cells converts fragmented mitochondria populations to a filamentous shape. Our studies highlight the genomic complexity of the locus, a newly identified transcript and ERMCS protein, Eliosin with a role in mitochondria dynamics and potential impact in ADPKD progression."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • PKD1 • PRKD1

Identification of novel genetic variants in hypertrophic cardiomyopathy. (PubMed, Cardiol Young) - "She was diagnosed with hypertrophic cardiomyopathy, confirmed by echocardiogram and cardiac MRI. Genetic testing revealed a variant of unknown significance in exon 7 of the FHL1 gene and exon 43 of the ANK2 gene."

Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • ANK2

Whole Exome Sequencing Identifies Novel Splicing Variants in the PTPRQ Gene and Their Mechanisms in Autosomal Recessive Non-Syndromic Hearing Loss. (PubMed, J Otol) - "Minigene assays and Sanger sequencing confirmed that the c.6603-3 T > G variant caused exon 43 skipping, resulting in a frameshift mutation (p.Ser2201ArgfsTer112)...This study identifies a novel compound heterozygous splicing variant in the PTPRQ gene in a Chinese family with DFNB84A, expanding the known spectrum of PTPRQ mutations. These findings enhance the understanding of PTPRQ-related hearing loss and may aid in early diagnosis, prevention, and therapeutic strategies."

Journal • Otorhinolaryngology

Synergy between RNA editing and alternative splicing modulates the biological properties of the voltage-gated calcium channel CaV1.3. (PubMed, J Biol Chem) - "Alternative splicing of exon 43 within the CaV1.3 C-terminus produces long (CaV1.3L) and short (CaV1.343S) variants exhibiting distinct gating and pharmacological properties...Functional analysis revealed that A-to-I RNA editing markedly decreases current density and induces a depolarizing shift in the current window, aligning the edited short variant's properties with those of the long variant. Our findings suggest that A-to-I RNA editing serves as a physiological mechanism regulating the 'short' gating properties of the CaV1.343S variant and positions A-to-I RNA editing of CaV1.343S variant as a neuroprotective physiological mechanism that prevents Ca2+ overload, especially in neurons susceptible to Ca2+ toxicity."

Journal • CNS Disorders • CAV1

Molecular Analysis of Congenital Adrenal Hyperplasia-X Syndrome and Development of a Pilot Panel for Analyzing Structural Variations with Long-Read Sequencing (ENDO 2024) - "Two patients carried heterozygous mutations p.S4175N in exon 43, which is an unclassified type... This study identified 8 patients with CAH-X syndrome carrying four different TNXA/TNXB chimeras by long-range PCR. Long-read sequencing emerged as a comprehensive and efficient method for the molecular analysis of CAH, especially for the identification of structural variations. Biallelic deletion of TNXB was associated with severe clinical manifestations."

Biomarker • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genetic Disorders • CYP1A2

Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene. (PubMed, Mob DNA) - "To our knowledge, this is the first report of a mobile element insertion into the coding sequence of EYS, as a likely cause of arRP in a family. Our study highlights the value of LRS technology in characterizing and identifying hidden pathogenic SVs, such as retrotransposon insertions, whose contribution to the etiopathogenesis of rare diseases may be underestimated."

Journal • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Rare Diseases • Retinal Disorders • Retinitis Pigmentosa

Clinical phenotype and genetic analysis of six Chinese patients affected with Acromicric dysplasia due to variants of FBN1 gene (PubMed, Zhonghua Yi Xue Yi Chuan Xue Za Zhi) - "All of the six patients had severe short stature and a variety of other clinical manifestations, which may be attributed to the variants of the FBN1 gene."

Journal • Hepatology • FBN1

Eliosin, A Protein Encoded by a Transcript from the HmPKD Locus, Is a Component of Mitochondria-ER Contact Sites/Mitochondria-Associated Membranes (MAMs) (KIDNEY WEEK 2023) - "This transcript has a splice from the 3' end of exon 41 to the 5' end of exon 43 of the HmPKD1 gene... Eliosin is a 48 kDa protein that is a component of mitochondria-ER membrane contact sites, and it acts to displace dynamin-related protein-1 from MAMs. We conclude that Eliosin plays a role in altering the balance between mitochondria fusion and scission. This finding extends the HmPKD1 locus' role in mitochondria metabolic physiology."

PKD1 • PRKD1

Rapid and Reliable Quantification of Prime Editing Targeting Within the Porcine ABCA4 Gene Using a Bioluminescence Resonance Energy Transfer-Based Sensor. (PubMed, Nucleic Acid Ther) - "Using a custom-made bioluminescence resonance energy transfer (BRET)-based editing sensor in HEK293 cells, we tested 27 different prime editing guide RNAs (pegRNAs) and additional 4 nicking guide RNAs (ngRNAs) with regard to their efficiency to induce sequences changes in exon 43 of the porcine ATP binding cassette subfamily A member 4 (ABCA4) gene that eliminate a mutagenic adenine frameshift insertion, which has been associated with STGD in humans. We identified nine working pegRNAs, and in combination with ngRNAs, we achieved a correction rate of up to ≈92% measured with the BRET-based reporter system. Our data prove the high efficiency of prime editors to correct mutations and highlight the importance of optimal ngRNA design, thus offering a promising editing tool to correct ABCA4 mutations in the disease context."

Journal • Preclinical • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Two novel CACNA1F gene mutations cause two different phenotypes: Aland Eye Disease and incomplete Congenital Stationary Night Blindness. (PubMed, Exp Eye Res) - "In Patient 2 variant c.5156G > C localized in the donor's splicing site of exon 43 was identified...Clinical spectrum is more severe and resembles the AIED phenotype when the mutation affects the first part of the protein, while it is more similar to CSNB2 if the mutation is localized at the end of the protein. Genetic testing results to be an essential tool to provide more accurate diagnosis and prognosis in patients with inherited retinal degenerative disorders and could help, in the future, to develop more specific therapeutic strategies."

Journal • Inherited Retinal Dystrophy • Ophthalmology

Critical prenatal diagnosis and management of incidental exon 43-44 deletion in the dystrophin gene. (PubMed, Eur J Obstet Gynecol Reprod Biol) - No abstract available

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[VIRTUAL] Eliosin, a Protein Encoded by a Transcript from the HmPKD1 Locus, Is a Component of Mitochondria-Endoplasmic Reticulum Contact Sites (MAMs) and Repairs Mitochondria Fragmentation in Polycystic Kidney Disease 12-7 Cells (KIDNEY WEEK 2021) - "This transcript has a splice from the 3’ end of exon 41 to the 5’ end of exon 43...Based on these findings we conclude that Eliosin plays a role in altering the balance between mitochondria fusion and scission. This finding extends the HmPKD1 locus role in mitochondria metabolic physiology."

Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • PRKD1

"or these POLE:NM_006231:exon43:c.G5860A:p.D1954N POLE:NM_006231:exon26:c.G3224A:p.S1075N POLE:NM_006231:exon18:c.G1935A:p.M645I" (@ShimaghavimiMD)

Novel and very rare causative variants in the COL7A1 gene of Vietnamese patients with recessive dystrophic epidermolysis bullosa revealed by whole-exome sequencing. (PubMed, Mol Genet Genomic Med) - "Our finding expands the spectrum of COL7A1 mutations and reports altered splicing at c.4518+2delT during the processing of the pre-mRNA. This study provides an additional scientific basis for diagnosis, genetic counseling, and prognosis purposes of EB patients."

Clinical • Journal • Genetic Disorders • Mood Disorders

Genotype Profile of Global EYS-Associated Inherited Retinal Dystrophy and Clinical Findings in a Large Chinese Cohort. (PubMed, Front Cell Dev Biol) - "The most common pathogenic variant was a frameshift c.4957dupA (p.S1653Kfs2) in exon 26, with an allele frequency of 12.7% (107/841), followed by c.8805C > A (p.Y2935X) in exon 43, with an allele frequency of 5.9% (50/841)...Clinical examinations revealed a typical progression of RPE atrophy from the peripheral area to the macula. This large global cohort of 420 IRD cases, with 262 distinct variants, identified genotype-phenotype correlations and mutation spectra with hotspots in the EYS gene."

Clinical • Journal • Inherited Retinal Dystrophy • Ophthalmology

Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles. (PubMed, BMC Nephrol) - "We confirm the power of URECs as a tool for functional studies on candidate variants in inherited renal disease, especially when the expression of the gene of interest is restricted to the kidney and we describe, for the first time, ciliary abnormalities in ARPKD patient cells."

Clinical • Journal • Chronic Kidney Disease • Cystic Fibrosis • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity. (PubMed, Mol Biol Rep) - "Genetic analysis yielded a homozygous splicing mutation (c.4597-2A>G) in the dysferlin gene, giving rise to the suppression of 28 bp of the exon 43. The splicing mutation found in our family (c.4597-2A>G) is responsible for the suppression of 28 bp of the exon 43 and a wide clinical intra-familial variability."

Heterogeneity • Journal • Myositis

The analysis of DMD gene deletions by multiplex PCR in Indonesian DMD/BMD patients: the era of personalized medicine. (PubMed, BMC Res Notes) - "Seventy-eight percent of deletions were clustered in the hot-spot region of exon 43 to 52...Therefore, multiplex PCR is one feasible method to detect DMD gene deletion in Indonesian DMD/BMD patients that can further determine the potential amenability of exon skipping therapy. In addition, this study is the first report of DMD gene deletion analysis in Indonesia."

Clinical • Journal

Fusion of the COL1A1 and FYN Genes in Epithelioid Osteoblastoma. (PubMed, Cancer Genomics Proteomics) - "A COL1A1-FYN fusion gene was found in an epithelioid osteoblastoma resulting in deregulation of FYN. Whether COL1A1-FYN represents a consistent genetic feature of epithelioid osteoblastomas, remains to be seen."

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