The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance
Mira Brazane
(1)
,
Dilyana Dimitrova
(1)
,
Julien Pigeon
(2)
,
Chiara Paolantoni
(3)
,
Tao Ye
(4)
,
Virginie Marchand
(5)
,
Bruno da Silva
(1)
,
Elise Schaefer
(6)
,
Margarita Angelova
(1)
,
Zornitza Stark
(7, 8)
,
Martin Delatycki
(7, 8)
,
Tracy Dudding-Byth
(9)
,
Jozef Gecz
(10, 11)
,
Pierre-Yves Plaçais
(12)
,
Laure Teysset
(1)
,
Thomas Préat
(12)
,
Amélie Piton
(4)
,
Bassem Hassan
(2)
,
Jean-Yves Roignant
(3, 13)
,
Yuri Motorin
(14)
,
Clément Carré
(1)
1
LBD -
Laboratoire de Biologie du Développement [IBPS]
2 ICM - Institut du Cerveau = Paris Brain Institute
3 CIG - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 IBSLor - Ingénierie, Biologie et Santé en Lorraine
6 IGMA - Institut de génétique médicale d’Alsace
7 MCRI - Murdoch Children's Research Institute
8 University of Melbourne
9 UoN - University of Newcastle [Callaghan, Australia]
10 University of South Australia [Adelaide]
11 SAHMRI - South Australian Health and Medical Research Institute [ Adelaide]
12 PdC - Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249)
13 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
14 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
2 ICM - Institut du Cerveau = Paris Brain Institute
3 CIG - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 IBSLor - Ingénierie, Biologie et Santé en Lorraine
6 IGMA - Institut de génétique médicale d’Alsace
7 MCRI - Murdoch Children's Research Institute
8 University of Melbourne
9 UoN - University of Newcastle [Callaghan, Australia]
10 University of South Australia [Adelaide]
11 SAHMRI - South Australian Health and Medical Research Institute [ Adelaide]
12 PdC - Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249)
13 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
14 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
Mira Brazane
- Fonction : Auteur
- PersonId : 799560
- ORCID : 0000-0002-0638-4020
Julien Pigeon
- Fonction : Auteur
- PersonId : 1222082
- ORCID : 0000-0002-5980-704X
- IdRef : 27935732X
Tao Ye
- Fonction : Auteur
- PersonId : 765367
- IdHAL : tao-ye
- ORCID : 0000-0002-3394-2083
Virginie Marchand
- Fonction : Auteur
- PersonId : 20993
- IdHAL : virginie-marchand
- ORCID : 0000-0002-8537-1139
- IdRef : 105659908
Elise Schaefer
- Fonction : Auteur
- PersonId : 1222083
- ORCID : 0000-0003-1004-6814
Margarita Angelova
- Fonction : Auteur
- PersonId : 799253
- ORCID : 0000-0002-0046-9891
Zornitza Stark
- Fonction : Auteur
- PersonId : 1222084
- ORCID : 0000-0001-8640-1371
Jozef Gecz
- Fonction : Auteur
- PersonId : 761724
- ORCID : 0000-0002-7884-6861
Laure Teysset
- Fonction : Auteur
- PersonId : 757505
- ORCID : 0000-0002-7413-1850
- IdRef : 182001962
Thomas Préat
- Fonction : Auteur
- PersonId : 916306
- IdHAL : thomas-preat
- ORCID : 0000-0001-9976-1763
- IdRef : 068719280
Bassem Hassan
- Fonction : Auteur
- PersonId : 819460
- ORCID : 0000-0001-9533-4908
- IdRef : 164842624
Jean-Yves Roignant
- Fonction : Auteur
- PersonId : 794512
- ORCID : 0000-0003-1395-2150
- IdRef : 089048261
Yuri Motorin
- Fonction : Auteur
- PersonId : 16579
- IdHAL : yuri-motorin
- ORCID : 0000-0002-8018-334X
- IdRef : 134883004
Clément Carré
- Fonction : Auteur
- PersonId : 756042
- ORCID : 0000-0002-9668-4288
- IdRef : 110775597
Résumé
FTSJ1 is a conserved human 2′-O-methyltransferase (Nm-MTase) that modifies several tRNAs at position 32 and the wobble position 34 in the anticodon loop. Its loss of function has been linked to X-linked intellectual disability (XLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here, we report a novel FTSJ1 pathogenic variant from an X-linked intellectual disability patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation on all human tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neural progenitor cells into neurons displays long and thin spine neurites compared with control cells. These defects are also observed in Drosophila and are associated with long-term memory deficits. Altogether, our study adds insight into FTSJ1 pathologies in humans and flies by the identification of novel FTSJ1 targets and the defect in neuron morphology.