Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency

Abstract

The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.

Snow White and the Seven Dwarfs: a fairytale for endocrinologists

“…In humans, a differentiating diagnosis between PROP1 and POU1F1 patients can be the presence or absence of gonadotropin deficiency, respectively, in addition to low GH, TSH, and PRL (46). In our 'study group', the candidate genes related to the phenotypic characteristics are PROP1 (47,48).…”

Practical implications of positive test for PROP1 mutation in hypopituitarism – case report

“…Przysadka u pacjentów z mutacją PROP1 ma wykształcone wszystkie struktury, tj. położony eutopowo płat przedni, płat tylny i lejek, jedynie wielkość może ją różnić od zdrowych osób [20]. Najczęściej mamy do czynienia z hipolub rzadziej hiperplazją jej gruczołowej części [3,23,24].…”

“…Wraz z wiekiem dochodzi do spontanicznej inwolucji, co skutkuje ostateczną hipoplazją gruczołu, prowadząc nawet do objawów pustego siodła. Czasem jest to poprzedzone zjawiskiem zwiększania i zmniejszania się "masy" w obrębie siodła tureckiego, niekiedy też niszczeniem siodła [2,19,20]. U pacjentów z niedoborem czynnika PROP1 opisywano dodatkowe odrębności w obrazie MRI przysadki, między innymi wskazywano na odmienną intensywność sygnału, jednakże nie wykazano korelacji między rozmiarem czy sygnałem przysadki a jej funkcją [18][19][20][24][25][26].…”

“…Typowe objawy tego defektu u ludzi to niedobór GH, TSH, PRL, gonadotropin (LH i FSH) a także, choć rzadziej i później, ACTH. Obraz kliniczny jest bardzo zróżnicowany nawet u blisko spokrewnionych pacjentów z tą samą mutacją PROP1 [20]. [21,22,27].…”

Advances in understanding hypopituitarism

“…Genetic alterations of PROP1 are usually associated with non-syndromic pituitary deficiencies. Nevertheless, dysfunction of this transcription factor can cause a variety of different phenotypes probably due to residual activity of altered protein synthesis 13 . Mutations in the non-pituitary-specific transcription factor HESX1 are commonly associated with syndromic clinical features and have been linked to septo-optic dysplasia.…”