Abstract:
OBJECTIVE:Mutations in HESX1 represent a rare cause of GH deficiency (GHD) associated with a broad spectrum of other anomalies. We searched for causative mutations in a cohort of 244 Italian patients affected by combined and isolated GHD (IGHD). METHODS:The HESX1 gene-coding region and exon-intron boundaries were screened by denaturing HPLC scanning. RESULTS:A novel mutation adjacent to the invariant donor splice site of intron 2 (c.357+3G>A) was identified at the heterozygous state in an IGHD patient. The in vitro and in vivo mRNA analysis of the wild-type HESX1 allele revealed the presence of the whole cDNA and two isoforms lacking exon 2 and exons 2-3 respectively. The mutant HESX1 allele yielded only two splicing products, the whole cDNA and the cDNA missing exons 2-3, whereas the mRNA lacking exon 2 was absent. An in vitro assay demonstrated that the exon 2-deleted mRNA, predicting a prematurely truncated protein, is subjected to nonsense-mediated mRNA decay (NMD). CONCLUSIONS:The c.357+3G>A mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. The mutation is likely to cause IGHD in the heterozygous patient by interfering with the downregulation of HESX1 expression mediated by alternative splicing and NMD. Our results open new insight into the mechanism of HESX1 regulation suggesting that the coupling of alternative splicing and NMD might play a fundamental role in directing the HESX1 expression, and that the alteration of this process might lead to severe consequences.
journal_name
Eur J Endocrinoljournal_title
European journal of endocrinologyauthors
Vivenza D,Godi M,Faienza MF,Mellone S,Moia S,Rapa A,Petri A,Bellone S,Riccomagno S,Cavallo L,Giordano M,Bona Gdoi
10.1530/EJE-11-0047subject
Has Abstractpub_date
2011-05-01 00:00:00pages
705-13issue
5eissn
0804-4643issn
1479-683Xpii
EJE-11-0047journal_volume
164pub_type
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journal_title:European journal of endocrinology
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pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
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pub_type: 杂志文章
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journal_title:European journal of endocrinology
pub_type: 临床试验,杂志文章
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更新日期:2003-07-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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更新日期:2018-08-01 00:00:00
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journal_title:European journal of endocrinology
pub_type: 杂志文章
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更新日期:2009-11-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2018-03-01 00:00:00
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pub_type: 临床试验,杂志文章,多中心研究
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pub_type: 杂志文章
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更新日期:2008-09-01 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:1995-04-01 00:00:00
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更新日期:2004-06-01 00:00:00
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更新日期:2009-04-01 00:00:00