A homozygous hypomorphic BNIP1 variant causes an increase in autophagosomes and reduced autophagic flux and results in a spondylo‐epiphyseal dysplasia

Bhavani, Gandham SriLakshmi and Shah, Hitesh Hasmukhalal and Kausthubham, Neethukrishna and Shukla, Anju and Katta, Girisha M (2022) A homozygous hypomorphic BNIP1 variant causes an increase in autophagosomes and reduced autophagic flux and results in a spondylo‐epiphyseal dysplasia. Human Mutation, 43. pp. 625-64. ISSN 1059-7794

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Abstract

BNIP1 (BCL2 interacting protein 1) is a soluble N‐ethylmaleimide‐sensitive factor‐attachment protein receptor involved in ER membrane fusion. We identified the homozygous BNIP1 intronic variant c.84+3A>T in the apparently unrelated patients 1 and 2 with disproportionate short stature. Radiographs showed abnormalities affecting both the axial and appendicular skeleton and spondylo‐epiphyseal dysplasia. We detected ~80% aberrantly spliced BNIP1 pre‐mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% in patient 1 compared to control fibroblasts. The BNIP1 ortholog in Drosophila, Sec20, regulates autophagy and lysosomal degradation. We assessed lysosome positioning and identified a decrease in lysosomes in the perinuclear region and an increase in the cell periphery in patient 1 cells. Immunofluorescence microscopy and immunoblotting demonstrated an increase in LC3B‐positive structures and LC3B‐II levels, respectively, in patient 1 fibroblasts under steady‐state condition. Treatment of serum‐starved fibroblasts with or without bafilomycin A1 identified significantly decreased autophagic flux in patient 1 cells. Our data suggest a block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts. BNIP1 together with RAB33B and VPS16, disease genes for Smith‐McCort dysplasia 2 and a multisystem disorder with short stature, respectively, highlight the importance of autophagy in skeletal development

Item Type: Article
Uncontrolled Keywords: Autophagolysosome; BNIP1; Exome sequencing; Retrograde vesicular transport; Syntaxin 18
Subjects: Medicine > KMC Manipal > Medical Genetics
Medicine > KMC Manipal > Orthopaedics
Depositing User: KMC Library
Date Deposited: 18 Jul 2022 03:54
Last Modified: 18 Jul 2022 03:54
URI: http://eprints.manipal.edu/id/eprint/158963

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