Combined Pituitary Hormone Deficiency Caused by Compound Heterozygosity for Two Novel Mutations in the POU Domain of the PIT1/POU1F1 Gene1

• Published in: The journal of clinical endocrinology and metabolism Vol. 86; no. 4; pp. 1545 - 1550
• Main Authors: Hendriks-Stegeman, Brenda I., Augustijn, Kevin D., Bakker, Bert, Holthuizen, Pieternella, van der Vliet, Peter C., Jansen, Maarten
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.04.2001
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.4.7371

The POU homeodomain containing transcriptional activator POU1F1, formerly called Pit1 or GHF-1, is required for the embryological determination and postnatal secretory function of the GH-, PRL-, and TSH-producing cells in the anterior pituitary. Several mutations in the gene encoding POU1F1 have been described, resulting in a syndrome of combined pituitary hormone deficiency involving these three hormones. Most of the patients with this phenotype have either a dominant negative mutation in codon 271 (R271W) or are homozygous for a recessive mutation in the POU1F1 gene; to date only one case has been reported with compound heterozygosity for two point mutations. Here, we describe a boy with severe deficiencies of GH, PRL, and TSH who had compound heterozygosity for two novel point mutations in the POU1F1 gene: a 1-bp deletion frameshift mutation (747delA), the first one described to date in this gene, which leads to a nonfunctional truncated protein lacking the entire DNA recognition helix of the POU homeodomain, and a missense mutation in the C-terminal end of the fourth α-helix of the POU-specific domain (W193R),which causes a 500-fold reduction in the ability to bind to DNA and activate transcription.