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Recessive variants in MYO1C as a potential novel cause of proteinuric kidney disease.
Elmubarak, Izzeldin; Shril, Shirlee; Mansour, Bshara; Bao, Aaron; Kolvenbach, Caroline M; Kari, Jameela A; Shalaby, Mohamed A; El Desoky, Sherif; Hildebrandt, Friedhelm; Schneider, Ronen.
Afiliación
  • Elmubarak I; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Shril S; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Mansour B; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Bao A; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kolvenbach CM; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kari JA; Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
  • Shalaby MA; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
  • El Desoky S; Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
  • Hildebrandt F; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
  • Schneider R; Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
Pediatr Nephrol ; 39(10): 2939-2945, 2024 Oct.
Article en En | MEDLINE | ID: mdl-38904753
ABSTRACT

BACKGROUND:

Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS).

METHODS:

To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS.

RESULTS:

We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants.

CONCLUSION:

We here identified recessive variants in MYO1C as a potential novel cause of NS in children.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Miosina Tipo I / Secuenciación del Exoma / Síndrome Nefrótico Límite: Adolescent / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Pediatr Nephrol Asunto de la revista: NEFROLOGIA / PEDIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Miosina Tipo I / Secuenciación del Exoma / Síndrome Nefrótico Límite: Adolescent / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Pediatr Nephrol Asunto de la revista: NEFROLOGIA / PEDIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania