<i>PROP1, HESX1, POU1F1, LHX3 </i>and<i> LHX4</i> Mutation and Deletion Screening and <i>GH1 </i>P89L and IVS3+1/+2 Mutation Screening in a Dutch Nationwide Cohort of Patients with Combined Pituitary Hormone Deficiency

Abstract

Background/Aims: Mutation frequencies of genes involved in combined pituitary hormone deficiency (CPHD) vary substantially between populations. The HYPOPIT study aims to obtain an overall picture of known and new genetic defects and variations in a nationwide cohort of Dutch (mostly) sporadic CPHD patients. Methods: We screened 79 CPHD patients from 78 families (regardless of MRI and hormonal phenotype) for mutations and deletions in PROP1, HESX1, POU1F1, LHX3 and LHX4, as well as the P89L and IVS3+1/+2 mutations in GH1, recently described to cause pituitary hormone impairment in addition to GH deficiency. Results: We did not find any mutation or deletion in PROP1, HESX1, LHX3 or LHX4, nor GH1 P89L and GH1 IVS3+1/+2 mutations. Among 12 patients with a typical ‘POU1F1 phenotype’, 1 patient was formerly known to have a POU1F1 mutation. This results in a POU1F1 mutation frequency in these patients of 8.3%. Conclusion: Thorough screening for mutations and deletions in PROP1, HESX1, POU1F1, LHX3, LHX4, as well as screening for GH1 P89L or GH1 IVS3+1/+2 mutations, did not reveal any genetic defect in our cohort of CPHD patients except for one formerly known POU1F1 mutation in 1 patient. Future research should focus on alternative explanations for CPHD, like other genes or environmental factors.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

“…The dramatic geographic clustering of the respective subjects in the selected parts of the world (Supplementary Table 1), illustrated by 70% prevalence of c.[301_302delAG] in Lithuanian patients with CPHD 10 and no patient with the PROP1 anomaly from Netherlands, 27 suggests a founder effect. On the other hand, the c.[301_302delAG] variant is located in three tandem GA repeats and such genetic regions are prone to polymerase slippage during DNA replication.…”

A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve

“…We directly sequenced the complete coding region and intron-exon boundaries of OTX2 in DNA samples from 92 patients with CPHD, in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out (19). Clinical characteristics and magnetic resonance imaging (MRI) data of the patients have been published previously (19).…”

“…Clinical characteristics and magnetic resonance imaging (MRI) data of the patients have been published previously (19).…”

“…DNA samples were collected from 92 patients with CPHD, who participated in the Dutch HYPOPIT study (19). These patients had been recruited from the Endocrinology Departments of six university and two non-university Hospitals and had been registered in the Dutch National Registry of Growth Hormone Treatment between 1992 and 2003.…”

Genetically Determined Central Hypothyroidism

“…This transcription factor is a member of the paired like homeodomain proteins, functions as a transcriptional repressor and is essential for normal forebrain development. Mutations in HESX1 gene have been described in patients with various forms of hypopituitarism with or without septo-optic dysplasia (SOD) [47][48][49][50]. Depending on the mutation, the disorder is inherited either as a dominant trait with incomplete penetrance or as a recessive trait.…”