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

Abstract

Combined pituitary hormone deficiency is characterized by the impaired production of pituitary hormones, commonly including growth hormone. The pathomechanism of the childhood-onset form of this disorder may involve germline mutations of genes encoding pituitary transcription factors, of which PROP1 gene mutations have been studied most extensively. However, controversy exists about the significance of PROP1 gene mutations, as both low and high frequencies have been reported in these patients. Because the different results may be related to differences in patient populations and/or the variability of clinical phenotypes, we performed the present study to examine the prevalence and spectrum of PROP1 gene mutations in 35 patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone deficiency. Genetic testing indicated the presence of disease-causing mutations in exons 2 and 3 of the PROP1 gene in 15 patients (43% of all patients; homozygous mutations in 10 patients and compound heterozygous mutations in 5 patients). Comparison of clinical data of patients with and without PROP1 gene mutations failed to show significant differences, except an earlier growth retardation detected in patients with PROP1 gene mutations. In one patient with PROP1 gene mutation, radiologic imaging showed an enlargement of the anterior lobe of the pituitary, whereas the other patients had hypoplastic or normal pituitary gland. All patients with PROP1 gene mutations had normal posterior pituitary lobe by radiologic imaging. These results indicate that using our inclusion criteria for genetic testing, PROP1 gene mutations can be detected in a high proportion of Hungarian patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone defect.

Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency

“…The Arg120Cys missense mutation had previously always been found in a homozygous state [10,20,22,[33][34][35] and was shown to lead to a protein with 12% retained function [33]. The Phe117Ile mutation has been observed in heterozygous state with other PROP1 mutations [33] or homozygous state [31] and was found to produce a protein with a 5% binding capacity as compared to normal [33]. The sister of this sibling pair was Phe117Ile heterozygous and was asymptomatic confirming the recessive mode of inheritance.…”

“…Moreover, the frequency of PROP1 mutations in CPHD has been reported from several countries to range from 0% in 2 studies from Australia and the United Kingdom [17,30] to as much as 43% in a study from Hungary [31] with an incidence of positive results ranging between 5 and 20% in most studies [8,[11][12][13][14]20]. The incidence of recessive mutations is known to vary in populations; for instance congenital adrenal hyperplasia is more common in some populations [32].…”

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

“…The data used were the level of allelic association between variant alleles and surrounding markers obtained by haplotype analyses. The input parameters were the recombination rates derived from Rutgers Combined Map 20 , the estimated frequencies of the mutant alleles in the present populations (0.003 for c. [150delA] carriers derived from epidemiological studies 10,22 (see Supplementary Tables 3 and 4 for the values assumed in each population). We performed a joint maximumlikelihood estimation of the age of the studied variants as well as the population growth rates assuming neutrality.…”

Genetikai tényezők a hypopituitarismus kialakulásában. A transzkripciós faktorok szerepe az agyalapimirigy-elégtelenség hátterében

“…Saját vizsgálatunkban 35, gyermekkorban manifesztálódó CPHD-s beteg PROP1-gén-szekvenciaanalízisét elvé-gezve, 15 beteg esetében (43%) igazolódott PROP1-gén-mutáció [17,18]. Az adenohypophysis organogenezisét irányító transzkripciós faktorok jellegzetes kaszkádjában a PROP1 transzkripciós fehérje expressziója a HESX1 expresszió-jának csökkenését (transzkripciós represszor hatás), majd néhány nappal később a pituitary-specific positive transcription factor 1 (Pit1, vagy más néven a POU domain, class 1, transcription factor 1 [POU1F1]) expresszióját okozza (transzkripciós aktivátor funkció) [19].…”