Two new PROP1 gene mutations responsible for compound pituitary hormone deficiency

Abstract

Mutations in the Prophet of Pit-1 (Prop-1), a paired-like homeodomain transcription factor involved in the early embryonic pituitary development, have been reported as a cause of combined hormone deficiency (CPHD) involving growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), gonadotrophins and in some cases adrenocorticotrophic hormone (ACTH). We report two pre-pubertal siblings with short stature and deficiency of GH and TSH at presentation. Molecular analysis of the PROP1 gene revealed compound heterozygotes for two novel missense mutations of the PROP1 gene affecting the same amino acid (Arg71Cys and Arg71His) in the first alpha helix of the Prop-1 homeodomain.

Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

“…/n.a. /damaging Ho: 0.255 (1) cHe: 2.296 (9) 29 c.211C>T p.Arg71Cys missense cHe 32 [ 55 ] 0.255 (1) 0.128 (1); [ – /– /3.3E–3 /2.0E–3] Damaging /damaging /damaging 30 c.217C>T p.Arg73Cys missense Ho [ 56 ] 0.510 (2) 0.510 (4); [ – /– /8.3E–4 /7.2E–4] Damaging /damaging /damaging 31 c.295C>T p.Arg99Ter nonsense Ho, cHe 32 [ 57 ] 0.510 (2) 0.383 (3); [ – /– /– /7.2E–4] n.a. /n.a.…”

The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism

“…All affected individuals exhibit recessive inheritance, and most mutations identified to date involve the DNA binding homeodomain which is highly conserved between mouse and human sharing 91% identity at the nucleotide level (36,40). These include three nonsense, (41)(42)(43), nine missense (36,40,(43)(44)(45)(46)(47)(48), seven frameshift mutations (36,41,45,(49)(50)(51)(52)(53), and two splice site mutations which disrupt normal exon splicing (40,54), in addition to a complete deletion of the gene (55) ( Table II). The majority of these mutations are predicted to result in complete loss of function of the protein by ablating DNA binding and transcriptional activation.…”

A novel PROP1 gene mutation (157delA) in Japanese siblings with combined anterior pituitary hormone deficiency

“…The younger brother (II-2) first presented with short stature (83·7 cm, − 2·7 SD) at 3 years of age with a bone age of 1 year 6 months. He was euthyroid (Table 2) but, as shown in Table 3, et al, 1998a;Deladoey et al, 1999;Krzisnik et al,1999;Riepe et al, 2001;Voutetakis et al, 2004a 157delA 1 This report R73C 3 3 Duquesnoy et al, 1998;Deladoey et al, 1999;Vallette-Kasic et al, 2001;Paracchini et al Cogan et al, 1998;Duquesnoy et al, 1998;Fofanova et al,1998a,b;Wu et al, 1998;Deladoey et al, 1999;Mendonca et al, 1999;Nogueira et al, 1999;Rosenbloom et al, 1999;Asteria et al, 2000;Pernasetti et al, 2000;Riepe et al, 2001;Vallette-Kasic et al, 2001;Lamesch et al, 2002;Pavel et al, 2003;Voutetakis et al, 2004a,b IVS2(− 2)A>T 2 Duquesnoy et al, 1998;Deladoey et al, 1999 F117I 1 1 Wu et al, 1998;Deladoey et al, 1999 R120C 4 1 Fluck et al, 1998;Wu et al, 1998;Deladoey et al, 1999;Arroyo et al, 2002 150delA, 301delAG, IVS2(− 2)A>T are also called 149delGA, 296delGA, A>T nt343-2, respectively (Duquesnoy et al, 1998;Fofanova et al, 1998a;Deladoey et al, 1999;Mody et al, 2002). his serum GH failed to reach normal levels after stimulation by hypoglycaemia or glucagon plus propranolol, his serum TSH level was...…”

“…To date, 12 mutations have been reported in more than 30 independent families and 20 sporadic cases mainly from Europe and North America (Table 1 and Fig. 3) (Cogan et al ., 1998; Duquesnoy et al ., 1998; Fluck et al ., 1998; Fofanova et al ., 1998a,b; Wu et al ., 1998; Deladoey et al ., 1999; Krzisnik et al ., 1999; Mendonca et al ., 1999; Rosenbloom et al ., 1999; Agarwal et al ., 2000; Asteria et al ., 2000; Osorio et al ., 2000; Pernasetti et al ., 2000; Riepe et al ., 2001; Vallette‐Kasic et al ., 2001; Arroyo et al ., 2002; Lamesch et al ., 2002; Mody et al ., 2002; Paracchini et al ., 2003; Vieira et al ., 2003; Voutetakis et al ., 2004a,b). This raises three questions: (i) Does the discrepancy of the reported number of cases between Asians and Caucasians reflect the condition's actual frequency?…”