"Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency

As pituitary function depends on the integrity of the hypothalamic-pituitar y axis, any defect in the development and organogenesis of this gland may a ccount 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, ma ny other homeodomain and transcription factors have been characterized as b eing involved in differ ent developmental stages of pituitary gland develop ment, 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 f rom different forms of CPHD for PROP1 gene alterations, and second to defin e possible hot spots and the frequency of the different gene alterations fo und. Of 73 subjects (36 families) analyzed, we found 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PRO P1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be ca used 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 29 6delGA, respectively. All but 1 mutation were located in the PROP1 gene enc oding the homeodomain. Importantly, 3 tandem repeats of the dinucleotides G A at location 296-302 in the PROP1 gene represent a hot spot for CPHD. In c onclusion, the PROP1 gene seems to be a major candidate gene for CPHD; howe ver, further studies are needed to evaluate other genetic defects involved in pituitary development.