Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin

TY - JOUR

T1 - Walking with giants

T2 - The challenges of variant impact assessment in the giant sarcomeric protein titin

AU - Weston, Timir G.R.

AU - Rees, Martin

AU - Gautel, Mathias

AU - Fraternali, Franca

N1 - Publisher Copyright: © 2023 The Authors. WIREs Mechanisms of Disease published by Wiley Periodicals LLC.

PY - 2024/3/1

Y1 - 2024/3/1

N2 - Titin, the so-called “third filament” of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well-documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants—those that result in a single amino-acid substitution in coding regions—reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin-related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well-studied giant proteins. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology.

AB - Titin, the so-called “third filament” of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well-documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants—those that result in a single amino-acid substitution in coding regions—reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin-related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well-studied giant proteins. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology.

KW - disease

KW - missense variant

KW - protein

KW - sarcomere

KW - titin

UR - http://www.scopus.com/inward/record.url?scp=85180866221&partnerID=8YFLogxK

U2 - 10.1002/wsbm.1638

DO - 10.1002/wsbm.1638

M3 - Review article

C2 - 38155593

AN - SCOPUS:85180866221

SN - 2692-9368

VL - 16

JO - WIREs Mechanisms of Disease

JF - WIREs Mechanisms of Disease

IS - 2

M1 - e1638

ER -