Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients

Abstract

The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature

“…It should be pointed out that the GHD can also be caused by variants in the genes encoding early or late transcription factors (PROP1 and POU1F1), as well as other genes [9,26,27]. However, it should be emphasized that variants of these genes, unlike in the case of GHD caused by GH1 or GHRHR variants, are usually associated with deficiencies of other pituitary hormones, such as prolactin, thyroid stimulating hormone, or even gonadotropins (LH, FSH) [19].…”

Congenital hypopituitarism due to novel compound heterozygous POU1F1 gene mutation: A case report and review of the literature

“…To date, there are only few reports on congenital hypopituitarism with POU1F1 gene mutation ( Fig. 3 , Table 1 ) [ 3 , 4 , [6] , [7] , [8] , [9] , [10] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] ]. In the earlier reports, the R271W mutation was firstly recognized within numerous patients, suspicious as a hot spot [ 8 , [12] , [13] , [14] , [15] , [16] ].…”

“…There are many genes that are considered as transcription factors to participate in signaling pathway of pituitary development accounting for 5–20% of congenital hypopituitarism. POU1F1 mutation accounts for 0.4–20% in these mutations [ [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] ]. Here, we report an 8-month-old patient of novel compound heterozygous POU1F1 gene mutation leading to congenital hypopituitarism, with the presentation of hypoglycemia, failure to thrive, and developmental delay.…”

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

“…Although much has been learned about pituitary development from mouse models, the etiology can only be identified in a minority of patients with congenital hypopituitarism. In some affected patients, monogenic etiologies have been identified, including genetic defects that are often recessive in HESX1 ( Thomas et al, 2001 ), PROP1 ( Wu et al, 1998 ; Correa et al, 2019 ), POU1F1 ( Turton et al, 2005 ; Birla et al, 2019 ), LHX3 ( Rajab et al, 2008 ; Jullien et al, 2019 ), and LHX4 ( Tajima et al, 2007 ). However, a monogenic etiology can be identified in fewer than 10% of cases ( Castinetti et al, 2015 ); in the remainder, the etiology is generally unclear.…”