A Familial Form of Congenital Hypopituitarism Due to aPROP1Mutation in a Large Kindred: Phenotypic andin VitroFunctional Studies

Abstract

We report the natural history of a hypopituitarism in a large Tunisian kindred including 29 subjects from the same consanguineous family. The index case was a 9-yr-old girl with severe growth retardation due to complete GH deficiency and partial corticotroph, lactotroph, and thyrotroph deficiencies. Magnetic resonance imaging showed a hyperplastic anterior pituitary. Thirteen of the 28 relatives examined (10 female subjects) had hypopituitarism. In the 14 patients, previously untreated (aged 6-53 yr), height was -5.7 +/- 1.7 sd score, and puberty was spontaneously initiated in only two females. Complete GH deficiency was found in all 12 patients investigated, of whom 11 had thyrotroph and eight of 10 had corticotroph deficiency. A homozygous R73C mutation of PROP1 was present in all 10 patients studied, and a heterozygous mutation was found in six unaffected parents or siblings. In vitro the mutant had 11.5% of the transactivation capacity of the wild type and was unable to bind to a high-affinity DNA sequence. This report showed the deleterious effect of the recessive R73C mutation that affects a hot spot of the PROP1 gene and was associated with severe dwarfism, a lack of spontaneous puberty, and a high incidence of early onset of corticotroph deficiency.

Hypothalamic and pituitary development: novel insights into the aetiology

“…The majority of these mutations are predicted to result in complete loss of function of the protein by ablating DNA binding and transcriptional activation. However, in vitro analysis has shown that some missense mutations retain partial activity (76,81,82). By far, the most common mutation (50-72% of all familial PROP1 mutations) (77,78,83), detected in multiple unrelated families from several different countries, is a 2 bp deletion among three tandem GA repeats ( 296 -GAGAGAG-302 ) within exon 2 resulting in a frameshift at codon 101 and the introduction of a termination codon at position 109 (often referred to as S109X), and probably represents a mutational hot spot within the gene, rather than a single common founder mutation (84).…”

Pituitary development: a complex, temporal regulated process dependent on specific transcriptional factors

“…This cell lineage is the most distinct among the pituitary cells (Reynaud et al 2004). In response to FGF8 signalling, corticotrope progenitors do not express any of the rostro-dorsal-specific TFs.…”

Evaluation of pituitary imaging in patients with PROP-1 gene mutation

“…Skirtingų literatūros šaltinių duomenimis, izoliuoto hipopituitarizmo (arba izoliuoto augimo hormono deficito) paplitimas vertinamas nuo 1:4000 iki 1:10 000 gyvagimių dėl hipofizės gaminamo augimo hormono arba jo geno patologijos ir sąlygoja augimo sutrikimą (1)(2)(3)(4). Dauginis hipopituitarizmas (DHP) pasitaiko rečiau -1:8000 gyvagimių arba dar rečiau (5-7), bet jo klinikiniai simptomai yra ryškesni: tokiems pacientams kartu su augimo sutrikimu randama centrinė hipotirozė, hipogonadotropinis hipogonadizmas, gali išryš-kėti ir antrinis antinksčių nepakankamumas.…”

“…Šį geną sudaro trys egzonai, koduojantys 226 amino rūgščių baltymą. PROP-1 geno ekspresija yra reikalinga genų programos aktyvavimui, kuri indukuoja ventralinę hipofizės proliferaciją ir pagrindinių adenohipofizės ląstelių diferenciaciją (3,10).…”

“…Iš dažniausiai žinomų 19 PROP-1 geno mutacijų dažniausiai pasitaiko šios: 301-302delGA (DGA 301/302) (2 egzonas); 358C>T (R120C) (3 egzonas); 296G>A (R99Q) (2 egzonas) ir 217C>T (R73C) (2 egzonas) (3,11).…”