Novel GLIS3 mutations demonstrate an extended multisystem phenotype

Abstract

Introduction: Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism. Subjects: We report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1-2 (case 1) or exons 1-4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2. Conclusions: Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a nonconsanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

“…Recent studies have linked mutations in the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) gene to a syndrome characterized by neonatal diabetes and congenital hypothyroidism that can include a wider spectrum of abnormalities, such as mild mental retardation and polycystic kidney disease (24)(25)(26)(27)(28)(29). Similar phenotypes have been observed in Glis3-deficient mice (29)(30)(31)(32)(33)(34)(35).…”

“…These observations indicate that GLIS3 is required for the TSH/TSHR-mediated induction of several genes critical for TH biosynthesis. Genetic variants and mutations in Nis, Pds, Tpo, and Duoxa2 have been linked to hypothyroidism (9,(20)(21)(22)(23)40); the observed decrease in the expression of these genes is therefore, at least in part, responsible for the development of hypothyroidism in Glis3KO mice and would explain the development of congenital hypothyroidism in the group of GLIS3 patients with dyshormonogenesis (24)(25)(26)(27)(28)37).…”

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

“…In addition to neonatal diabetes, congenital hypothyroidism and polycystic kidneys, they presented a broad spectrum of clinical phenotypes. These include craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, choanal atresia, sensorineural deafness and exocrine pancreatic insufficiency (Dimitri et al 2011(Dimitri et al , 2015. They further described facial dysmorphism including bilateral low-set ears, depressed nasal bridge, elongated and upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in some patients (Dimitri et al 2016).…”

Congenital Hypothyroidism due to Thyroid Dysgenesis: From Epidemiology to Molecular Mechanisms

“…a mutation-carrier parent is unaffected) 55,[57][58][59][60][61] . Other genes (GLIS3, URB1, SALL1 and TBX1) are mutated in syndromes where thyroid dysfunction is associated with other dysmorphisms and is generally mild, except for GLIS3 patients, which can have severe CH 80,81 .…”