JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects

Filippis, Tiziana de; Marelli, Federica; Nebbia, Gabriella; Porazzi, Patrizia; Corbetta, Sabrina; Fugazzola, Laura; Gastaldi, Roberto; Vigone, Maria Cristina; Biffanti, Roberta; Frizziero, Daniela; Mandarà, Luana; Prontera, Paolo; Salerno, Mariacarolina; Maghnie, Mohamad; Tiso, Natascia; Radetti, Giorgio; Weber, Giovanna; Persani, Luca

doi:10.1210/jc.2015-3403

Cited by 67 publications

(45 citation statements)

References 26 publications

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“…Human heterozygous loss‐of‐function JAG1 mutations are associated with Alagille syndrome type 1 (ALGS1), which is characterized by variable involvement of liver, heart, skeleton, eye and facial defects. Evaluation of thyroid function in 21 cases with Alagille syndrome showed that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including TD …”

Section: Molecular Defects Associated To Td In Humansmentioning

confidence: 99%

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Molecular defects in thyroid dysgenesis

et al. 2019

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Congenital hypothyroidism (CH) is a neonatal endocrine disorder that might occur as itself or be associated to congenital extra-thyroidal defects. About 85% of affected subjects experience thyroid dysgenesis (TD), characterized by defect in thyroid gland development. In vivo experiments on null mice paved the way for the identification of genes involved thyroid morphogenesis and development, whose mutation has been strongly associated to TD. Most of them are thyroid-specific transcription fac-

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Section: Molecular Defects Associated To Td In Humansmentioning

confidence: 99%

“…Evaluation of thyroid function in 21 cases with Alagille syndrome showed that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including TD. 59…”

Section: Glis3mentioning

confidence: 99%

Molecular defects in thyroid dysgenesis

et al. 2019

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“…Congenital thyroid dysfunction may also arise in the context of other complex disorders, such as Alagille syndrome type 1 due to JAG1 mutations (ALGS1) [35] and hepatic or parotid massive hemangiomas, which may produce the thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase [36, 37]. …”

Section: Mild Hypothyroidism In Neonatesmentioning

confidence: 99%

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

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Capalbo

Weber

et al. 2018

Journal of the Endocrine Society

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Mild hypothyroidism, also known as subclinical hypothyroidism (SH), is biochemically defined as serum TSH levels above the upper limit of the reference range, in the presence of normal serum concentrations of total T4 and free T4 (FT4). In the neonatal period, mild hypothyroidism can be defined by the presence of a TSH value between 6 and 20 mIU/L and normal FT4 levels. After the neonatal period, SH can be defined mild if TSH ranges between 4.5 and 10 mIU/L. The management of mild hypothyroidism in childhood is challenging. The major concern is to establish whether this condition should always be considered an expression of mild thyroid dysfunction. Indeed, the effects of untreated mild hypothyroidism are still not completely defined. In the neonatal period, concern exists about neurocognitive outcome; in children, although there is no clear evidence of alterations in growth or neurocognitive development, subtle cardiovascular abnormalities have been documented. Therefore, there is still uncertainty about the need of treatment across all ages, and the management should be based on the age of the child, the etiology, and the degree of TSH elevation, as well as on other patient factors. This review updates current evidences on diagnosis and management of mild hypothyroidism in childhood.

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“…Abnormalities at any step of thyroid development may result in TD associated with hypothyroidism or not (Maiorana et al , ). Previous studies of sporadic and familial TD covering a wide clinical spectrum identified mutations in nine genes: PAX8 , NKX2‐1 , FOXE1 , NKX2‐5 , TSHR, GLIS3, NTN1 , JAG1 and BOREALIN (Dentice et al , ; Senée et al , ; Carré et al , , , ; Sura‐Trueba et al , ; Ramos et al , ; Opitz et al , ; de Filippis et al , ). However, mutations in these genes are found in only 5% of all patients with TD and identification of causative mutations remains a challenging task.…”

Section: Introductionmentioning

confidence: 99%

TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

et al. 2018

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The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.

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JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects

Abstract: clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.

Cited by 67 publications

References 26 publications

Molecular defects in thyroid dysgenesis

Molecular defects in thyroid dysgenesis

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

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