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Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism

Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism
Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism
Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.
0002-9297
833-849
Woods-Townsend, Kathryn
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Cundall, Maria
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Turton, James
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Rizotti, Karine
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Mehta, Ameeta
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Palmer, Rodger
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Wong, Jacqueline
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Chong, W.K.
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Al-Zyoud, Mahmoud
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El-Ali, Maryam
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Otonkoski, Timo
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Martinez-Barbera, Juan-Pedro
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Thomas, Paul Q.
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Robinson, Iain C.
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Lovell-Badge, Robin
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Woodward, Karen J.
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Dattani, Mehul T.
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Woods-Townsend, Kathryn
af927fa3-30b6-47d9-8b4d-4d254b3a7aab
Cundall, Maria
d5e045bb-2485-467a-a9f3-87aa6c6e4908
Turton, James
cd107069-77e8-4ea7-a985-b8334bbf386e
Rizotti, Karine
ee13b557-ee34-4262-9b06-f59dabda796a
Mehta, Ameeta
e168bd92-07e4-40bc-b121-6ff255b36502
Palmer, Rodger
834901dd-7817-4fd3-b92c-2095972545d8
Wong, Jacqueline
a06a5899-a67f-4352-8f44-9a04ebb07325
Chong, W.K.
4f1a14d2-d6d8-4a6b-9466-3651b9682b48
Al-Zyoud, Mahmoud
f714d17a-5bc3-41cf-be30-71bc7d808ca7
El-Ali, Maryam
0a782e06-14ea-4d87-9bef-db2a7c01e3bd
Otonkoski, Timo
72031d9b-8c45-46c2-a1e3-13c72bf1e977
Martinez-Barbera, Juan-Pedro
667454bc-6e29-4a5c-ac6f-6d48d057db1c
Thomas, Paul Q.
ec86495c-a951-4817-8c3c-44c4599599b2
Robinson, Iain C.
45aac566-f630-4156-8536-1fb92165b881
Lovell-Badge, Robin
bffcf0f3-b67e-4c5f-8d11-15d0084dd0d9
Woodward, Karen J.
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Dattani, Mehul T.
536002c2-9284-4800-95db-65375bb0afbd

Woods-Townsend, Kathryn, Cundall, Maria, Turton, James, Rizotti, Karine, Mehta, Ameeta, Palmer, Rodger, Wong, Jacqueline, Chong, W.K., Al-Zyoud, Mahmoud, El-Ali, Maryam, Otonkoski, Timo, Martinez-Barbera, Juan-Pedro, Thomas, Paul Q., Robinson, Iain C., Lovell-Badge, Robin, Woodward, Karen J. and Dattani, Mehul T. (2005) Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. The American Journal of Human Genetics, 76 (5), 833-849. (PMID:10473124)

Record type: Article

Abstract

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

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1-s2.0-S0002929707607290-main.pdf__tid=2ab58032-d39f-11e4-934d-00000aab0f27&acdnat=1427364310_b5bdf7d4cbc7043a4861c213c110bf0e - Version of Record
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More information

Accepted/In Press date: 9 March 2005
Published date: May 2005
Organisations: Southampton Education School, Mathematics, Science & Health Education

Identifiers

Local EPrints ID: 340434
URI: http://eprints.soton.ac.uk/id/eprint/340434
ISSN: 0002-9297
PURE UUID: c7c8f96d-cc85-487e-9f2c-7289ef212975
ORCID for Kathryn Woods-Townsend: ORCID iD orcid.org/0000-0003-3376-6988

Catalogue record

Date deposited: 26 Mar 2015 10:09
Last modified: 21 Nov 2021 02:57

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Contributors

Author: Maria Cundall
Author: James Turton
Author: Karine Rizotti
Author: Ameeta Mehta
Author: Rodger Palmer
Author: Jacqueline Wong
Author: W.K. Chong
Author: Mahmoud Al-Zyoud
Author: Maryam El-Ali
Author: Timo Otonkoski
Author: Juan-Pedro Martinez-Barbera
Author: Paul Q. Thomas
Author: Iain C. Robinson
Author: Robin Lovell-Badge
Author: Karen J. Woodward
Author: Mehul T. Dattani

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