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.
Highlights
Intellectual disability (ID) is defined by significant limitations in intellectual performance and a reduction of conceptual, social and practical skills with an onset before the age of 18
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
As expected for a mouse model for non-syndromic intellectual disability we did not observe genotype specific anatomical differences or differences in organ weight when normalized to body weight
Summary
Intellectual disability (ID) is defined by significant limitations in intellectual performance (intelligence quotient < 70) and a reduction of conceptual, social and practical skills with an onset before the age of 18. ID was separated into syndromic and nonsyndromic forms, with the former being ID in the presence of clinically consistent features. The non-syndromic forms seem more common, but as more patients with similar gene defects are molecularly diagnosed syndromic features may become apparent. ID has genetic as well as environmental causes (like excessive alcohol consumption during pregnancy), severe forms are often caused by genetic defects in single genes [2,3,4]. Monogenic recessive causes of ID have been excessively studied in X-linked forms and with the development of next-generation-sequencing techniques the elucidation of autosomal forms has made a leap forward. Mutation discovery studies so far have clearly shown that ID is genetically and functionally heterogeneous and that several ID proteins interact, are involved in the same process or target the same substrate. One emerging “ID gene group” is involved in tRNA modifications and includes NSUN2 [5,6,7], ADAT3 [8], TRMT10A [9,10], TRIT1 [11], TRMT1 [3], ELP2 [3,12], PUS3 [13], MTO1 [14] and FTSJ1 [15,16,17,18]
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Schedule a callMore From: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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