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

Tess Holling, Gandham S. Bhavani, Leonie von Elsner, Hitesh Shah, Neethukrishna Kausthubham, Shaila S. Bhattacharyya, Anju Shukla, Geert R. Mortier, Thorsten Schinke, Tatyana Danyukova, Sandra Pohl, Kerstin Kutsche, Katta M. Girisha

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)625-642
Number of pages18
JournalHuman Mutation
Volume43
Issue number5
DOIs
Publication statusPublished - 05-2022

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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