Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

Taha, Doris; Barbar, Maha; Kanaan, Hassan; Balfe, J. Williamson

doi:10.1002/ajmg.a.20267

Cited by 66 publications

(50 citation statements)

References 21 publications

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“…ZF5 is critical for the binding of Glis3 to Glis-BS and therefore for its transcriptional activity (3). We show that Glis3 mutant mice exhibit abnormalities very similar to those displayed by NDH1 patients (45,47), including a greatly reduced life span and development of polycystic kidneys and neonatal diabetes.…”

mentioning

confidence: 62%

“…Glis1-3 proteins are expressed in a spatial and temporal manner during embryonic development, suggesting that they regulate specific physiological processes (25,27,28,30,39,56). Loss of Glis2 function in mice and mutations in GLIS2 have been associated with nephronophthisis (2,26), while genetic alterations in the GLIS3 gene have been linked to a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) (45,47).…”

mentioning

confidence: 99%

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Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

Kang

Beak²,

Kim³

et al. 2009

Molecular and Cellular Biology

108

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In this study, we describe the generation and partial characterization of Krüppel-like zinc finger protein Glis3 mutant (Glis3 zf/zf ) mice. These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease. We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway. Although Glis3 zf/zf mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium. We further show that Glis3 interacts with the transcriptional modulator Wwtr1/TAZ, which itself has been implicated in glomerulocystic kidney disease. Wwtr1 recognizes a P/LPXY motif in the C terminus of Glis3 and enhances Glis3-mediated transcriptional activation, indicating that Wwtr1 functions as a coactivator of Glis3. Mutations in the P/LPXY motif abrogate the interaction with Wwtr1 and the transcriptional activity of Glis3, indicating that this motif is part of the transcription activation domain of Glis3. Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions. We propose that localization to the primary cilium and interaction with Wwtr1 are key elements of the Glis3 signaling pathway.

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mentioning

confidence: 62%

mentioning

confidence: 99%

Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

Kang

Beak²,

Kim³

et al. 2009

Molecular and Cellular Biology

108

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“…Maternal thyroid function was normal. As with patient 1, suppression of TSH proved difficult despite consistently normal free T 4 measurements on 14 mg/kg per day T 4 . Serum TSH concentration remains at 40-60 mIU/l despite normal free T 4 on 15 mg/kg per day T 4 .…”

Section: Casementioning

confidence: 77%

“…These patients died from infection in infancy, but recently, patients with deletions within the GLIS3 gene have presented with a milder phenotype consisting of diabetes and hypothyroidism in the neonatal period, but with no hepatic or renal involvement. All children to date with GLIS3 mutations were born to consanguineous parents (3,4).…”

Section: Introductionmentioning

confidence: 99%

Novel GLIS3 mutations demonstrate an extended multisystem phenotype

Dimitri

Warner

Minton

et al. 2011

European Journal of Endocrinology

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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.

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“…Three affected children died at 10 days, 6 and 16 months of life, respectively (Taha et al 2003, Senee et al 2006. In 2006, Senée and coworkers identified a homozygous insertion (2067insC) in GLIS3 that underlies the neonatal diabetes syndrome in one family.…”

Section: Glis3 and Neonatal Diabetes Syndromementioning

confidence: 99%

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

Wen

Yang

2017

Journal of Molecular Endocrinology

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GLI-similar 3 (GLIS3), a member of the Krüppel-like zinc finger protein subfamily, is predominantly expressed in the pancreas, thyroid and kidney. Glis3 mRNA can be initially detected in mouse pancreas at embryonic day 11.5 and is largely restricted to β cells, pancreatic polypeptide-expressing cells, as well as ductal cells at later stage of pancreas development. Mutations in GLIS3 cause a neonatal diabetes syndrome, characterized by neonatal diabetes, congenital hypothyroidism and polycystic kidney.

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Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

Cited by 66 publications

References 21 publications

Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

Novel GLIS3 mutations demonstrate an extended multisystem phenotype

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

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