Endocrine Abstracts

Pituitary development is governed by activation of a cascade of transcription factors that orchestrate both pituitary morphogenesis and differentiation. Among them, loss of function of PROP1 is the most common genetic cause of combined pituitary hormone deficiency (CPHD) with two PROP1 gene variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) being most prevalent. We identified the homozygous c.[301_302delAG] variant in 70% out of 67 Lithuanian subjects with CPHD, suggesting a founder effect and precised their auxological and hormonal phenotype - normal birth lengths/weights, testicular retention in 31% of boys, and a progressive decline of median height SDS over years 1 – 5: –1.56, –2.34, –3.43, –3.52 and –3.70. Deficiencies of GH, TSH, ACTH and FSH/LH were diagnosed in 44/44, 44/44, 19/44 and 22/44 subjects at median age 5.5, 5.6, 13.1 and 15.0 years, respectively. In addition, we aimed to elucidate the origin of the two prevalent PROP1 variants. We studied 237 patients originating from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene. Haplotypes were reconstructed by Phase and Haploview software. We demonstrated the ancestral origin of both variants – c.[301_302delAG] originated in Lithuania ~ 101 generations ago (confidence interval 90.1 – 116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1 – 29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~ 13.8 (12.2 – 17.0) and 16.4 (14.4 – 20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4 – 52.7) generations ago at the territory of current Byelorussia. We confirmed that the most frequent variants in the PROP1 gene are founder variants that spread from Eastern/Central Europe overseas. That explains their unequal distribution among various populations.