A Dominant C150Y Mutation in FHL1 Induces Structural Alterations in LIM2 Domain Causing Protein Aggregation In Human and Drosophila Indirect Flight Muscles

Santhoshkumar, R and Preethish-Kumar, V and Mangalaparthi, KK and Unni, S and Padmanabhan, B and Keshava Prasad, TS and Nongthomba, U and Atchayaram, N and Narayanappa, G (2021) A Dominant C150Y Mutation in FHL1 Induces Structural Alterations in LIM2 Domain Causing Protein Aggregation In Human and Drosophila Indirect Flight Muscles. In: Journal of Molecular Neuroscience, 71 (11). pp. 2324-2335.

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Abstract

FHL1-related myopathies are rare X-linked dominant myopathies. Though clinically classified into several subgroups, spinal and scapuloperoneal muscle involvement are common to all. In this study, we identified c.449G > A, p.C150Y mutation by clinical exome sequencing in two patients from same family (son and mother) of Indian origin who presented with multiple contractures. Muscle biopsy showed numerous intracytoplasmic aggregates intensely stained on HE and MGT. The strong reactions to M-NBT revealed aggregates to be reducing bodies and positively labeled to anti-FHL1 antibody. Ultrastructurally, Z-band streaming and granular and granulofilamentous material were seen. Further, the translational evidence of mutant peptide was confirmed using mass spectrometric analysis. To establish p.C150Y as the cause for protein aggregation, in vivo studies were carried out using transgenic Drosophila model which highlighted Z-band abnormalities and protein aggregates in indirect flight muscles with compromised physiological function. Thus, recapitulating the X-linked human disease phenotype. Additionally, the molecular dynamics simulation analysis unraveled the drastic change in α-helix of LIM2, the region immediately next to site of C150Y mutation that could be the plausible cause for protein aggregation. To the best of our knowledge, this is the first study of p.C150Y mutation in FHL1 identified in Indian patients with in vivo and in silico analysis to establish the cause for protein aggregation in muscle.

Item Type:	Journal Article
Publication:	Journal of Molecular Neuroscience
Publisher:	Humana Press Inc.
Additional Information:	The copyright for this article belongs to Humana Press Inc.
Keywords:	Drosophila melanogaster; FHL1; Mass spectrometry; Molecular dynamics simulation; Mutation; Reducing body
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	18 Apr 2023 10:09
Last Modified:	18 Apr 2023 10:09
URI:	https://eprints.iisc.ac.in/id/eprint/80663

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