Homozygous deletion of TRMT10A as part of a contiguous gene deletion in a syndrome of failure to thrive, delayed puberty, intellectual disability and diabetes mellitus

Abstract

Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17-year-old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%-6.2%). RT-PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.

tRNA methyltransferase homologue gene TRMT10A mutation in young adult‐onset diabetes with intellectual disability, microcephaly and epilepsy

“… had hypoglycaemia, as did the individual reported by Zung et al . ; however, no hypoglycaemia was reported in our patients or in those reported by Igoillo‐Esteve et al . .…”

“… and Zung et al . . All the individuals had intellectual disability, and epilepsy was common except in the individual reported by Zung et al.…”

“…More recently, Zung et al . described an individual with TRMT10A deletion with failure to thrive, delayed puberty, intellectual disability and diabetes. In the present paper, we report the eighth and ninth individual from the fourth family known to have this syndrome as a result of a TRMT10A mutation.…”

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

“…In accordance with its localized function, mutations in TRMT10C cause mitochondrial disorders [166]. Association of mutations in TRMT10A with microcephaly and young onset diabetes reaffirms its regulatory role in lineage differentiation [167,168,169,170,171]. Basal levels of TRMT10A protein expression is observed in all tissues but is enriched in brain and pancreatic β cells accounting for the tissue-specific developmental disorders [167].…”

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”