Genetic 564 Undergraduate Capstone course at University of Wisconsin Madison
What is Congenital Hypothyroidism?
Congenital hypothyroidism is partial or complete loss of function of the thyroid gland from birth. The butterfly shaped gland is located in the lower neck region and individuals with congenital hypothyroidism the gland is either absent, misshapen, or reduced in size. [1] The main function of the thyroid gland is to produce iodine-containing hormones that participate in growth regulation, brain development and metabolism. Congenital hypothyroidism can be either a stand-alone disease or a symptom of other syndromes such as Pendred syndrome, Bamforth-Lazarus syndrome and brain-lung-thyroid syndrome. [7]
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Who is most affected by Congenital Hypothyroidism?1 in 3,000 newborns are affected with congenital hypothyroidism. [3] For unknown reasons females newborns are more than half as likely be diagnosed. Women with iodine deficiencies during pregnancy account for largest cause of congenital hypothyroidism in newborns. Genetically related cause only account for 15-20 percent, and 2-5 percent of which is hereditary. [4] Congenital hypothyroidism is an autosomal recessive disorder and follow traditional mendelian inheritance genetics.
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PAX 8 and the genetic link to Congenital Hypothyroidism
The PAX gene family is responsible for early embryonic tissue formation, PAX genes transcribe PAX transcription factors which regulate gene expression. PAX 8 (Paired-Box gene 8) is located on the long arm of the 2nd chromosome in Humans and other mammals. PAX8 is one of two known genes associated with congenital hypothyroidism, the other being TSHR gene. [2] The main function of PAX8 gene is to regulate growth and development of the thyroid gland and its hormone receptors. Mutations in PAX8 disrupt development of the thyroid gland resulting in loss of function, reduction in size or complete nonexistence. [5,6] Post birth PAX 8 continues to play a role in hormone production in healthy individuals, however those with Congenital Hypothyroidism continue to have a thyroid hormone deficit all their lives, the only treatment option being hormone replacement therapy.
The Importance of New Born Screening
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Author: Audrey Simard
Email: [email protected]
Institution: University of Wisconsin - Madison
Course Website: www.genetics564.weebly.com
Last Updated: May 11, 2017
Email: [email protected]
Institution: University of Wisconsin - Madison
Course Website: www.genetics564.weebly.com
Last Updated: May 11, 2017
References:
[1] Grasberger H, Ringkananont U, Lefrancois P, Abramowicz M, Vassart G, Refetoff S. Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Mol Endocrinol. 2005 Jul;19(7):1779-91. Epub 2005 Feb 17.
[2] Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro R. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998 May;19(1):83-6.
[3] Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May;42(5):379-89. Review.
[4] Pasca di Magliano M, Di Lauro R, Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13144-9
[5] Ramos HE, Carré A, Chevrier L, Szinnai G, Tron E, Cerqueira TL, Léger J, Cabrol S, Puel O, Queinnec C, De Roux N, Guillot L, Castanet M, Polak M. Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations. Eur J Endocrinol. 2014 Oct;171(4):499-507. doi: 10.1530/EJE-13-1006
[6] Tell G, Pellizzari L, Esposito G, Pucillo C, Macchia PE, Di Lauro R, Damante G. Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism. Biochem J. 1999 Jul 1;341( Pt 1)89-93
[7] Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab. 2001 Jan;86(1):234-8
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[2] Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro R. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998 May;19(1):83-6.
[3] Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May;42(5):379-89. Review.
[4] Pasca di Magliano M, Di Lauro R, Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13144-9
[5] Ramos HE, Carré A, Chevrier L, Szinnai G, Tron E, Cerqueira TL, Léger J, Cabrol S, Puel O, Queinnec C, De Roux N, Guillot L, Castanet M, Polak M. Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations. Eur J Endocrinol. 2014 Oct;171(4):499-507. doi: 10.1530/EJE-13-1006
[6] Tell G, Pellizzari L, Esposito G, Pucillo C, Macchia PE, Di Lauro R, Damante G. Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism. Biochem J. 1999 Jul 1;341( Pt 1)89-93
[7] Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab. 2001 Jan;86(1):234-8
Images:
Title Background: http://www.goodlivingwarehouse.com/