“Hot Spot” in the PROP1 Gene Responsible for Combined Pituitary Hormone Deficiency¹

Abstract

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD). Although pit-1 was 1 of the first factors identified as a cause of CPHD in mice, many other homeodomain and transcription factors have been characterized as being involved in different developmental stages of pituitary gland development, such as prophet of pit-1 (prop-1), P-Lim, ETS-1, and Brn 4. The aims of the present study were first to screen families and patients suffering from different forms of CPHD for PROP1 gene alterations, and second to define possible hot spots and the frequency of the different gene alterations found. Of 73 subjects (36 families) analyzed, we found 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PROP1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be caused by any 2-bp GA or AG deletion at either the 148-GGA-GGG-153 or 295-CGA-GAG-AGT-303 position. As any combination of a GA or AG deletion yields the same sequencing data, the frameshift mutations were called 149delGA and 296delGA, respectively. All but 1 mutation were located in the PROP1 gene encoding the homeodomain. Importantly, 3 tandem repeats of the dinucleotides GA at location 296-302 in the PROP1 gene represent a hot spot for CPHD. In conclusion, the PROP1 gene seems to be a major candidate gene for CPHD; however, further studies are needed to evaluate other genetic defects involved in pituitary development.

Long-Term Outcomes, Genetics, and Pituitary Morphology in Patients with Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiencies: A Single-Centre Experience of Four Decades of Growth Hormone Replacement

“…The highest frequencies of patients affected by PROP1 mutations were reported for East-Central and Eastern Europe [31], pointing to a founder effect. Most of the mutations identified so far are represented by just two gene variants: c.296delGA (previously referred to as c.301_302delGA) and c.150delA [32]. These typical mutations were also found in all three patients with PROP1 changes in our cohort.…”

High prevalence of PROP1 gene mutations in hungarian patients with childhood-onset combined anterior pituitary hormone deficiency

“…1). The three tandem repeats of the GA dinucle- otides at location 296-302 represent the "hot-spot" region for mutation, and mutations involving this region cause preterm truncation of the homeodomain (18,19).…”

“…Most reports indicate that in the Caucasian population PROP1 gene mutations are frequently found in patients with non-acquired, familial forms of CPHD (19,20,23). In a study reported from the Czech Republic, 18 of 74 patients with CPHD had homozygous or heterozygous mutations of the PROP1 gene (12).…”

“…Mutation analysis of the PROP1 gene was carried out using polymerase chain reaction (PCR) followed by direct bidirectional sequencing of the PCR-amplified DNA. The oligonucleotide primer pairs used for PCR amplification of exons 1-3 of the PROP1 gene were as described by Deladoey et al (19). The PCR-amplified DNA was purified using a commercial kit (High pure PCR product, Roche Diagnostics, Mannheim, Germany).…”

The natural history of the R120C PROP1 mutation reveals a wide phenotypic variability in two untreated adult brothers with combined pituitary hormone deficiency

“…PROP-1 is necessary for the activation of the POU1F-1 gene, the human homolog of mouse Pit-1 (13,14). Defects in the PROP-1 gene may cause deficiencies in pituitary hormones produced by POU1F-1-dependent cell lineages (somatotrophs, thyrotrophs, lactotrophs), as well as gonadotrophin and corticotrophin deficiencies (3)(4)(5)(15)(16)(17)(18).…”