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Clin Endocrinol (Oxf). 2012 Mar;76(3):387-93. doi: 10.1111/j.1365-2265.2011.04236.x.

Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency.

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  • 1Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.

Abstract

BACKGROUND:

  Mutations in the POU1F1 gene severely affect the development and function of the anterior pituitary gland and lead to combined pituitary hormone deficiency (CPHD).

OBJECTIVE:

  The clinical and genetic analysis of a patient presenting with CPHD and functional characterization of identified mutations.

PATIENT:

  We describe a male patient with extreme short stature, learning difficulties, anterior pituitary hypoplasia, secondary hypothyroidism and undetectable prolactin, growth hormone (GH) and insulin-like growth factor 1 (IGF1), with normal random cortisol.

DESIGN:

  The POU1F1 coding region was amplified by PCR and sequenced; the functional consequence of the mutations was analysed by cell transfection and in vitro assays.

RESULTS:

  Genetic analysis revealed compound heterozygosity for two novel putative loss of function mutations in POU1F1: a transition at position +3 of intron 1 [IVS1+3nt(A>G)] and a point mutation in exon 6 resulting in a substitution of arginine by tryptophan (R265W). Functional analysis revealed that IVS1+3nt(A>G) results in a reduction in the correctly spliced POU1F1 mRNA, which could be corrected by mutations of the +4, +5 and +6 nucleotides. Analysis of POU1F1(R265W) revealed complete loss of function resulting from severely reduced protein stability.

CONCLUSIONS:

  Combined pituitary hormone deficiency in this patient is caused by loss of POU1F1 function by two novel mechanisms, namely aberrant splicing (IVS1+3nt (A>G) and protein instability (R265W). Identification of the genetic basis of CPHD enabled the cessation of hydrocortisone therapy without the need for further assessment for evolving endocrinopathy.

© 2012 Blackwell Publishing Ltd.

PMID:
22010633
[PubMed - indexed for MEDLINE]
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