Abstract
Mutations in the X chromosomal tRNA 2′‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.
| Original language | English |
|---|---|
| Pages (from-to) | 2083-2093 |
| Number of pages | 11 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1865 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Sep 2019 |
Keywords
- Ftsj1
- Intellectual disability
- Mouse model
- X-linked
- tRNA methyltransferase
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
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A mouse model for intellectual disability caused by mutations in the X-linked 2′‑O‑methyltransferase Ftsj1 gene. / Jensen, Lars R.; Garrett, Lillian; Hölter, Sabine M.; Rathkolb, Birgit; Rácz, Ildikó; Adler, T.; Prehn, Cornelia; Hans, Wolfgang; Rozman, Jan; Becker, Lore; Aguilar-Pimentel, Juan Antonio; Puk, Oliver; Moreth, Kristin; Dopatka, Monika; Walther, Diego J.; von Bohlen und Halbach, V.; Rath, Matthias; Delatycki, Martin; Bert, Bettina; Fink, Heidrun; Blümlein, Katharina; Ralser, Markus; Van Dijck, Anke; Kooy, F.; Stark, Zornitza; Müller, Sabine; Scherthan, H.; Gecz, J.; Wurst, Wolfgang; Wolf, Eckhard; Zimmer, Andreas; Klingenspor, Martin; Graw, Jochen; Klopstock, Thomas; Busch, Dirk; Adamski, J.; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě; von Bohlen und Halbach, Oliver; Ropers, Hans Hilger; Kuss, Andreas W.
In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1865, No. 9, 01.09.2019, p. 2083-2093.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - A mouse model for intellectual disability caused by mutations in the X-linked 2′‑O‑methyltransferase Ftsj1 gene
AU - Jensen, Lars R.
AU - Garrett, Lillian
AU - Hölter, Sabine M.
AU - Rathkolb, Birgit
AU - Rácz, Ildikó
AU - Adler, T.
AU - Prehn, Cornelia
AU - Hans, Wolfgang
AU - Rozman, Jan
AU - Becker, Lore
AU - Aguilar-Pimentel, Juan Antonio
AU - Puk, Oliver
AU - Moreth, Kristin
AU - Dopatka, Monika
AU - Walther, Diego J.
AU - von Bohlen und Halbach, V.
AU - Rath, Matthias
AU - Delatycki, Martin
AU - Bert, Bettina
AU - Fink, Heidrun
AU - Blümlein, Katharina
AU - Ralser, Markus
AU - Van Dijck, Anke
AU - Kooy, F.
AU - Stark, Zornitza
AU - Müller, Sabine
AU - Scherthan, H.
AU - Gecz, J.
AU - Wurst, Wolfgang
AU - Wolf, Eckhard
AU - Zimmer, Andreas
AU - Klingenspor, Martin
AU - Graw, Jochen
AU - Klopstock, Thomas
AU - Busch, Dirk
AU - Adamski, J.
AU - Fuchs, Helmut
AU - Gailus-Durner, Valérie
AU - de Angelis, Martin Hrabě
AU - von Bohlen und Halbach, Oliver
AU - Ropers, Hans Hilger
AU - Kuss, Andreas W.
N1 - Funding Information: This work was supported by the German Federal Ministry of Education and Research [Infrafrontier grant 01KX1012 to MHdA] and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme [grant 01ZX1314H to W. Wurst], by the German Science Foundation Collaborative Research Centre (CRC) 870 and by the Helmholtz Portfolio Theme ‘Supercomputing and Modelling for the Human Brain’ (SMHB). Funding Information: We thank the patients and their families for their participation in the study. We also thank Bettina Lipkowitz, Marion Amende and the technicians at the animal facility at the Max Planck Institute for Molecular genetics, the GMC technicians as well as the GMC animal caretaker team for excellent technical assistance. We thank Robert Weissmann for help with the bioinformatic analysis. This work was supported by the German Federal Ministry of Education and Research [Infrafrontier grant 01KX1012 to MHdA] and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme [grant 01ZX1314H to W. Wurst], by the German Science Foundation Collaborative Research Centre (CRC) 870 and by the Helmholtz Portfolio Theme ?Supercomputing and Modelling for the Human Brain? (SMHB). None declared. Funding Information: We thank the patients and their families for their participation in the study. We also thank Bettina Lipkowitz, Marion Amende and the technicians at the animal facility at the Max Planck Institute for Molecular genetics, the GMC technicians as well as the GMC animal caretaker team for excellent technical assistance. We thank Robert Weissmann for help with the bioinformatic analysis. This work was supported by the German Federal Ministry of Education and Research [Infrafrontier grant 01KX1012 to MHdA] and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme [grant 01ZX1314H to W. Wurst], by the German Science Foundation Collaborative Research Centre (CRC) 870 and by the Helmholtz Portfolio Theme ‘Supercomputing and Modelling for the Human Brain’ (SMHB). None declared.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Mutations in the X chromosomal tRNA 2′‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.
AB - Mutations in the X chromosomal tRNA 2′‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.
KW - Ftsj1
KW - Intellectual disability
KW - Mouse model
KW - X-linked
KW - tRNA methyltransferase
UR - http://www.scopus.com/inward/record.url?scp=85064902079&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2018.12.011
DO - 10.1016/j.bbadis.2018.12.011
M3 - Article
C2 - 30557699
AN - SCOPUS:85064902079
VL - 1865
SP - 2083
EP - 2093
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 9
ER -