A pleiotropic recurrent dominant variant causes a complex multisystemic disease.

Date publication

septembre 2024

Journal

Science advances

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BAHRAM Siamak , Dr GOETZ Jacky , Dr CARAPITO Christine , Dr CARAPITO Raphaël

Tous les auteurs :
Molitor A, Lederle A, Radosavljevic M, Sapuru V, Zavorka Thomas ME, Yang J, Shirin M, Collin-Bund V, Jerabkova-Roda K, Miao Z, Bernard A, Rolli V, Grenot P, Castro CN, Rosenzwajg M, Lewis EG, Person R, Esperón-Moldes US, Kaare M, Nokelainen PT, Batzir NA, Hoffer GZ, Paul N, Stemmelen T, Naegely L, Hanauer A, Bibi-Triki S, Grün S, Jung S, Busnelli I, Tripolszki K, Al-Ali R, Ordonez N, Bauer P, Song E, Zajo K, Partida-Sanchez S, Robledo-Avila F, Kumanovics A, Louzoun Y, Hirschler A, Pichot A, Toker O, Mejía CAM, Parvaneh N, Knapp E, Hersh JH, Kenney H, Delmonte OM, Notarangelo LD, Goetz JG, Kahwash SB, Carapito C, Bajwa RPS, Thomas C, Ehl S, Isidor B, Carapito R, Abraham RS, Hite RK, Marcus N, Bertoli-Avella A, Bahram S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39270020

Résumé

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (), (), and () encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 lymphopenia, a quasi-absence of naïve CD4 and CD8 cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Mots clés

Humans, Inositol 1,4,5-Trisphosphate Receptors, genetics, Male, Female, Calcium, metabolism, Child, Mutation, Jurkat Cells, Child, Preschool, Genes, Dominant, Pedigree, Phenotype

Référence

Sci Adv. 2024 09 13;10(37):eado5545