Dataset Information

En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.

ABSTRACT: Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) sequence variants in LAMB3 gene. LAMB3 encodes LAMB3, the β subunit of epidermal-dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional translational readthrough-inducing drugs amplify endogenous PTC readthrough; however, translational readthrough-inducing drugs are either proteotoxic or nonselective. Ribosome editing is a more selective and less toxic strategy. This technique identified ribosomal protein L35/uL29 (ie, RpL35) and RpL35-ligands repurposable drugs artesunate and atazanavir as molecular tools to increase production levels of full-length LAMB3. To evaluate ligand activity in living cells, we monitored artesunate and atazanavir treatment by dual luciferase reporter assays. Production levels of full-length LAMB3 increased up to 200% upon artesunate treatment, up to 150% upon atazanavir treatment, and up to 170% upon combinatorial treatment of RpL35 ligands at reduced drug dosage, with an unrelated PTC reporter being nonresponsive. Proof of bioactivity of RpL35 ligands in selective increase of full-length LAMB3 provides the basis for an alternative, targeted therapeutic route to replenish LAMB3 in severe junctional epidermolysis bullosa.

SUBMITTER: Wimmer B

PROVIDER: S-EPMC10810840 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.

Wimmer Bjoern B Friedrich Andreas A Poeltner Katharina K Edobor Genevieve G Mosshammer Claudia C Temaj Gazmend G Rathner Adriana A Karl Thomas T Krauss Jan J von Hagen Joerg J Gerner Christopher C Breitenbach Michael M Hintner Helmut H Bauer Johann W JW Breitenbach-Koller Hannelore H

JID innovations : skin science from molecules to population health 20231110 1

Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) sequence variants in <i>LAMB3</i> gene. <i>LAMB3</i> encodes LAMB3, the β subunit of epidermal-dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional transla ...[more]

PMID: 38282649

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Project description:RationaleEpidermolysis bullosa (EB) refers to a group of rare inherited mechanobullous disorders that present with great clinical and genetic heterogeneity. Its severity ranges from mild blistering to life-threatening. However, the clinical symptoms of different types of EB overlap significantly, especially at an early stage. Thus it is important to clarify the diagnosis for prognostic implications, patient management, and genetic counseling.Patient concernsHere, we report a 10-day-old male neonate from a nonconsanguineous Chinese family. He showed a bulla on the left lower limb lasting for 3 days, erosions around fingertips and toe tips at birth (predominantly on fingers), with the progressive spread of generalized blisters over the body as well as the development of the illness.DiagnosisThe patient was diagnosed with suspected epidermolysis bullosa according to the blisters and erosions of the body as well as the pyogenic fingernails and toenails.InterventionsThe patient was performed targeted next-generation sequencing (NGS) with 9 candidate known genes, subsequently, his parents were screened for the mutations identified in the patient by Sanger sequencing. Then, prenatal diagnosis with amniotic fluid was performed in the subsequent pregnancy by Sanger sequencing.OutcomesTargeted NGS revealed a previously unreported splice site variant c.822+1G>A (IVS 8) and a known recurrent nonsense variant c.124C>T (p.Arg42Ter, exon 3) in LAMB3 gene. The patient's father possessed a heterozygous c.822+1G>A mutation, his mother possessed a heterozygous c.124C>T mutation. For the subsequent pregnancy, the analyses of amniotic fluid sample indicated that the fetus carried neither of the mutations.LessonsOur finding will further enlarge LAMB3 genotype-phenotype correlations spectrum. Targeted capture sequencing is a valuable method to illustrate precise molecular pathology in patients with EB disorders, especially at an early stage of the clinical evaluation of complex disorders to avoid unnecessary and economically wasteful tests.

Dataset Information

En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.

Publications

En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.

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