The formin INF2 in disease: progress from 10 years of research

Abstract

Formins are a conserved family of proteins that primarily act to form linear polymers of actin. Despite their importance to the normal functioning of the cytoskeleton, for a long time, the only two formin genes known to be a genetic cause of human disorders were DIAPH1 and DIAPH3, whose mutation causes two distinct forms of hereditary deafness. In the last 10 years, however, the formin INF2 has emerged as an important target of mutations responsible for the appearance of focal segmental glomerulosclerosis, which are histological lesions associated with glomerulus degeneration that often leads to end-stage renal disease. In some rare cases, focal segmental glomerulosclerosis concurs with Charcot–Marie–Tooth disease, which is a degenerative neurological disorder affecting peripheral nerves. All known INF2 gene mutations causing disease map to the exons encoding the amino-terminal domain. In this review, we summarize the structure, biochemical features and functions of INF2, conduct a systematic and comprehensive analysis of the pathogenic INF2 mutations, including a detailed study exon-by-exon of patient cases and mutations, address the impact of the pathogenic mutations on the structure, regulation and known functions of INF2, draw a series of conclusions that could be useful for INF2-related disease diagnosis, and suggest lines of research for future work on the molecular mechanisms by which INF2 causes disease.

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Abbreviations

aHUS:

Atypical hemolytic uremic syndrome

ARM:

Armadillo

CAP:

Cyclase-associated protein

CMT:

Charcot–Marie–Tooth

DAD:

Diaphanous autoinhibitory domain

DID:

Diaphanous inhibitory domain

ESRD:

End-stage renal disease

FH:

Formin homology

FSGS:

Focal segmental glomerulosclerosis

INF2:

Inverted formin 2

KAc-actin:

Lysine-acetylated actin

MCN:

Minimal change nephropathy

WH2:

Wiskott–Aldrich syndrome homology 2

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Acknowledgements

We thank Dr Phil Mason for revising the English language of the manuscript. We thank Cyrus Biotechnology Inc. for a free trial of the Cyrys Bench® software. Research in the laboratory of MAA is supported by a Grant (PGC2018-095643-B-I00) from the Ministerio de Ciencia e Innovación, Fondo Europeo de Desarrollo Regional y Agencia Estatal de Investigación. A contract (FPU16/00935) from the Ministerio de Ciencia e Innovación to LL-d-H is also acknowledged.

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Labat-de-Hoz, L., Alonso, M.A. The formin INF2 in disease: progress from 10 years of research. Cell. Mol. Life Sci. 77, 4581–4600 (2020). https://doi.org/10.1007/s00018-020-03550-7

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Keywords

  • Focal segmental glomerulosclerosis
  • Charcot–Marie–Tooth disease
  • Chronic kidney disease
  • Peripheral neuropathy
  • Genetic disorder
  • Actin