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Original Studies |
Division of Pediatric Endocrinology, University Children’s Hospital (J.D., C.F., B.V.K., A.E., P.E.M.), 3010 Bern, Switzerland; Dokuz Eylül Faculty of Medicine (A.B.), 35340 Izmir, Turkey; Cobbold Laboratories, Middlesex Hospital (P.C.H.), London, United Kingdom W1N 8AA; and Howard Hughes Medical Institute, University of California-San Diego (W.W.), La Jolla, California 92093-0648
Address all correspondence and requests for reprints to: Prof. Dr. Primus E. Mullis, Department of Pediatrics, Pediatric Endocrinology, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The aims of the present study were first to screen families and patients suffering from different forms of CPHD for PROP1 gene alterations and to determine the frequency of the different gene alterations, and second to define possible "hot spots" within the gene associated with this phenotype. Of 73 subjects analyzed, we found 35 patients with CPHD caused by a PROP1 gene defect. There were 3 different missense, 2 frameshift, and 1 splice site mutations resulting in the disorder. Although the occurrence of hormonal deficiency varies from patient to patient, even among those with the same gene mutation, the affected patients as adults were not only GH, PRL, and TSH deficient, but were also gonadotropin deficient (9).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty-six families with a total of 73 affected patients (41 males and 32 females) diagnosed with CPHD were studied. The parents of the children studied were unaffected and were of normal height and weight for age and sex (12). The criteria for CPHD included impaired production of GH and, in addition, a lack of 1 or more of the other hormones derived from the pituitary anterior gland. Although all CPHD patients were GH, PRL, TSH, and gonadotropin deficient in adulthood, there was a high phenotypic variability among these patients during infancy, childhood, and adolescence. Therefore, the inclusion criteria for this study, as far as the occurrence of the different hormonal deficiencies was concerned, were relatively open. Standard auxological assessment was performed (13). None of the affected patients had evidence of an organic disease, psycho-social deprivation, or any eating disorder, and all had normal renal and hepatic function. Informed consent was obtained from parents and all family members studied.
Hormonal assays
Study patients received GH provocative testing using only arginine stimulation before the age of 2 yr; thereafter, both arginine (0.5 mg/kg; Pharmacia & Upjohn, Stockholm, Sweden) and insulin-induced hypoglycemia (ITT; 0.15 U/kg, iv; Novo-Nordisk, Gentofte, Denmark), and adequate hypoglycemia (blood glucose, <2.0 mmol/L) were achieved in all cases. The stress of ITT normally results in an increased secretion of ACTH and, hence, cortisol. Basal cortisol and ACTH were measured before ITT, and peak values were assessed after the response to ITT. This test was combined with the exogenous administration of TRH (200 µg; Ferring, Malmø, Sweden) and GnRH (100 µg; Ferring) to test the remainder of the hypothalamic-pituitary axis. The criteria for GH deficiency included a peak GH level of less than 2 ng/mL after stimulation (arginine stimulation and ITT) and a height velocity below -2.5 SD score (12).
Stimulation tests
The stimulation tests were performed as described previously (14). Over the years, GH, TSH, LH, FSH, and PRL were measured using various assays, as previously described (9). However, we retested some of the samples using the methods that are now in use in our laboratory and compared the data with the results obtained using the "old" test procedures. The correlations among the different tests were between r = 0.81 and 0.96. Therefore, we state in detail the actual test procedures only.
GH assays
GH was measured using an immunoradiometric assay, HGH MAIAclone (Biodata Diagnostics, Freiburg, Germany), which incorporates two high affinity monoclonal antibodies. The interassay coefficients of variation (CVs) were 2.3%, 2.4%, and 2.2% at 2, 9, and 24 ng/mL, respectively. The intraassay CVs were 2%, 1.7%, and 1.7% at 2, 9, and 24 ng/mL.
TSH assay
TSH was measured by a TSH assay using automated direct chemiluminometric methodology (Chiron Diagnostics Corp., East Walpole, MA). Inter- and intraassay CVs were 6.1% and 4.3% at 0.3 mIU/L and 5.2% and 5.8% at 4.7 mIU/L, respectively.
LH and FSH assays
FSH and LH were measured using Dade fluorometric enzyme immunoassays (Stratus, Dade, Miami, FL). For FSH, inter- and intraassay CVs were 1.6% and 3.8% at 4 IU/L and 2.7% and 2.9% at 20 IU/L. Cross-reactivities between LH and TSH were 0.5% and 0.01%, respectively. For LH, inter- and intraassay CVs were 7.5% and 5.8% at 2.5 IU/L and 2% and 2.7% at 20 IU/L. Cross-reactivities between TSH and FSH were 0.02% and 0.001%, respectively.
PRL assay
PRL was measured using a fluorometric enzyme immunoassay (Stratus, Dade). Inter- and intraassay CVs were 5% and 4.3% at 4.5 µg/L and 4.8% and 3.2% at 59 µg/L, respectively.
ACTH and cortisol assays
ACTH measurements were performed using a immunometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The interassay CVs were 4.6% and 7.0% at 8.3 and 380 pg/mL, respectively. The intraassay CVs at 6.6 and 293 pg/mL were 3.4% and 3.8%. Cortisol was measured by fluorometric enzyme immunoassay (Stratus). The interassay CVs were 4.6%, 4.1%, and 4.9% at 115, 300, and 1000 nmol/L, respectively. The intraassay CVs at 115, 300, and 100 nmol/L were 7.2%, 5.1%, and 4.0%.
Genomic analysis of PROP1 gene
DNA was extracted from the peripheral lymphocytes as previously
reported (15). One hundred nanograms of human genomic DNA were used as
template in a 20-µL PCR. The coding sequence of PROP1 was
PCR amplified with a 5'-sense primer (5'-CGAACATTCAGAGACAGAGTCCCAGA-3')
and a 3'-antisense primer (5'-GAATTCACCATGATCTCCCA-3') to generate a
3.5-kb fragment. The reaction consisted of 1 min at 94 C, followed by
35 cycles of 30 s at 94 C, 30 s at 56 C, and 10 min at 68 C.
Thereafter, PCR products were purified by gel electrophoresis followed
by agarose gel DNA extraction. Direct sequencing of the double-stranded
PCR fragments was carried out according to the thermal cycle sequencing
protocol (PE Applied Biosystems, 373 DNA Sequencer,
Perkin Elmer, Rotkreuz, Switzerland) using a 5'-sense
primer (5'-TCTGGCCATGCTGAGAAG-3') and a 3'-antisense primer
(5'-TTCTAGTCGCTGAGCTGAC-5'). To sequence the exons individually,
exon-specific primers were designed (Table 1
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A diagnostic screening test was used to define a 2-bp deletion
(GA or AG) at nt position 295-CGA-GAG-AGT-303. As this location belongs
to exon 2, exon 2 was PCR amplified (Table 1
). Thereafter, samples of
the PCR-amplified product were digested to completion with the
restriction enzyme BcgI under the conditions recommended by
the commercial supplier (BioLabs, Bioconcept, Allschwil, Switzerland).
Any GA or AG deletion within that region introduces a BcgI
restriction site, and therefore, digestion of exon 2 PCR products
confirms the presence of an altered allele. After electrophoresis in
ethidium bromide-stained 2% (wt/vol) Metaphor gel (BioLabs), the DNA
fragments were photographed by UV transillumination. Having found an
altered PROP1 allele, the deletion was confirmed by
sequencing as described above. Furthermore, the frameshift mutations
were called 296delGA.
Controls
The PROP1 genes of 28 unrelated normal control individuals were directly sequenced to evaluate nt variations.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 36 families with 73 CPHD-affected patients, 35 patients (18
males and 17 females; 35 of 73; 48%) belonging to 18 unrelated
families (18 of 36; 50%) were found to have PROP1 gene
defects responsible for the disorder. The locations of the
PROP1 gene alterations are shown in Fig. 1, and the frequencies are summarized in
Table 2. The frequencies of given
PROP1 gene alterations among CPHD-affected subjects are
stated as percentages of the number of these patients (n = 35) and
their families (n = 18).
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). Screening for 296delGA
As depicted in Fig. 2, BcgI digestion of exon 2 PCR amplification products revealed
the 296delGA of the PROP1 based on the restriction digest
pattern. This method can easily be used to screen CPHD patients. All
data obtained were confirmed by direct sequencing.
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As indicated in Table 2, some of the PROP1 gene
alterations have been reported before. However, in this study two new
mutations were found. First, a nt C to T transition (CGC
TGC; C217T)
resulted in the substitution of ArgCys at codon 73 (exon 2). Second,
a nt A to T transition at the nt 2–343 position introduced an
intronic point mutation. Therefore, the invariant GA nt of the
splice-acceptor site was destroyed. These two new mutations are
depicted in Fig. 3.
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In patients presenting with any form of PROP1 gene
alteration, the development of hormonal deficiencies was studied in
great detail. Based on a great variability in phenotype, the secretion
of pituitary-derived hormones (GH, TSH, LH, and FSH) declined gradually
with age, following a different pattern and time scale in each
individual (Fig. 4).
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Whereas patients with the PROP1 gene defect presented
eventually with a lack not only of GH, PRL, and TSH, but also of LH and
FSH (Fig. 4), the cortisol production was normal (mean, 635 nmol/L;
range, 423–931 nmol/L) after insulin-induced hypoglycemia (mean, 1.2
mmol/L; range, 0.5–1.7 mmol/L). It is important to stress, however,
that in some of the patients (n = 7; three males and four
females), low levels of cortisol (mean, 120 nmol/L; range, 64–178
nmol/L) and ACTH (mean, 5 pg/mL; range, 5–21 pg/mL) were measured at
the beginning of the test.
Polymorphic sites
In addition, 28 unrelated normal control individuals were screened
for nt variations within the PROP1 gene. None of the 56
chromosomes analyzed carried a mutation/deletion as reported in
subjects with CPHD. However, 3 polymorphic sites in the
PROP1 gene were detected, 1 located in intron I which is
untranslated and the other 2 located in exons I and III (Table 3). The polymorphic site in exon 1 is
located at codon 9 (nt 27, GCTGCC), yielding an identical
substitution of alaninealanine (A9A). The site in exon 3 is at codon
142 (G to A transition at position 424; GCCACC) and replaces alanine
with threonine (A142T). This mutation is located 14 amino acids outside
of the homeodomain region (Fig. 1). In intron 1, the third nt can be
either adenine or guanine and remains untranslated. The frequencies of
the polymorphisms have been assessed and are presented in Table 3.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is most important to stress that the clinical phenotype of CPHD varies considerably, especially with respect to the occurrence and the severity of the different pituitary-derived hormone deficiencies (9, 23). This variability impedes the identification of genes that could be used for screening, presenting a difficulty in defining the gene defects causing the disorder. Molecular studies have revealed that only a minority of patients presenting with CPHD can be accounted for by structural defects in the POU1F1 gene. PROP1, because of its broad phenotype, is more likely a candidate gene.
The aim of this study was to define the prevalence and frequency of PROP1 gene alterations among patients suffering from different phenotypes of CPHD. To characterize the patients as CPH deficient, the time scale of the development of the hormonal deficiencies was not taken into consideration. All patients, however, were eventually GH, TSH, PRL, and gonadotropin deficient.
The prevalence of PROP1 gene alterations among patients with
CPHD was high. A PROP1 gene defect could be found in a total
of 35 of 73 patients (48%), representing 18 of 56 (32%) nonrelated
CPHD-affected subjects. Furthermore, these 35 patients with a
PROP1 gene defect belonged to 18 of 36 nonrelated
CPHD-affected families (50%). This specification of nonrelated
patients and/or families is of importance, because if 1 family is very
large and the others small, then the frequency of the reported mutation
in a large family is made artificially high. However, these data
suggest that the PROP1 gene is an important etiological
factor in CPHD. There was no correlation between phenotype and
genotype. The manifestation of the different deficiencies varied
substantially, as has been reported even in patients with the same C to
T transition resulting in the substitution of argininecysteine at
codon 120 (R120C) (9). Moreover, all of the patients became symptomatic
by exhibiting severe growth retardation and failure to thrive, mainly
caused by GH deficiency (n = 28; 80%); TSH deficiency was the
first symptom in 20% (n = 7). Thirteen patients (6 males and 7
females) entered puberty spontaneously. Although 6 girls experienced
menarche, they were rather late, at a mean age of 15.2 yr (range,
14.8–17.3 yr). The others, both males and females, needed hormonal
induction of pubertal development. Seven patients (3 males and 4
females) presented low basal levels of cortisol and ACTH; however, the
stimulated levels after insulin-induced hypoglycemia revealed no
abnormality. Therefore, a slight impairment of basal ACTH secretion
might be present in some of these patients, although none of the
patients ever presented with any sign of hypocortisolism, nor was any
replacement therapy necessary.
As presented in Fig. 1 and Table 2, we found three missense mutations
(n = 10 belonging to 4 of 36 unrelated families; 11%), 2
frameshift mutations within well defined regions (n = 24 belonging
to 13 of 36 families; 36%), and 1 splice site mutation (n = 1; 1
of 36; 2.7%) causing the CPHD phenotype. The missense mutation, C217T
(R73C), and the splice site mutation, nt 343–2 (A to T), are new,
whereas the other mutations/deletions have been previously reported
(7, 8, 9). Importantly, all but 1 mutation (149delGA) were located in the
gene fragment encoding the homeodomain of the PROP1 protein.
In detail, one family presented a homozygous C to T transition at
position 217 (C217T) at codon 73 in exon 2, predicting a missense
mutations (R73C). This missense mutation replaces a charged residue by
a neutral amino acid in a region highly conserved among all members of
the paired-like class of homeodomains (24, 25). Moreover,
this arginine residue, which is invariant in all of these proteins, is
conserved in 95% of the more than 450 homeodomain proteins known to
date (24, 25). In another family, a homozygous T to A transversion
resulted in an F117I substitution (7). It has been reported that the
phenyl-alanine (F) residue at codon 117 is part of the core DNA binding
motif of homeodomains and that it is almost invariant within the
homeodomain family (7). In two families, five patients presented the
argininecysteine substitution at codon 120 (R120C, amino acid 52 in
the third helix of homeodomain). None of the homeodomain proteins in
this family have a cysteine residue at this position (7, 25).
Furthermore, all of the frameshift mutations (149delGA; 296delGA) were
caused by a 2-bp deletion in exon 2, yielding an aberrant translation
product with a premature stop codon TAG at position 109 (S109X) in the
same exon (7, 8). Therefore, in all of these patients the PROP1 protein
is lacking 118 carboxyl-terminal amino acids. Preceding exon 3, an
intronic point mutation (A to T transition) involving the
splice-acceptor site was found. This mutation destroyed the
invariant AG nt of the splice-acceptor site, which is crucial for
normal splicing. In these patients, there is no splicing at the end of
intron 2, but a cryptic splice site within exon 3 may be activated.
Therefore, the translated protein lacks part of the homeodomain region,
leaving it without any effect. Moreover, as it is well known that
mutations occur disproportionately in CpG dinucleotides, two of the
three missense mutations were caused by a CGTG transition (26).
Furthermore, our data suggest that there is a hot spot region for PROP1 gene alterations. In 12 of 36 unrelated CPHD affected families (33.3%), the PROP1 gene defects found were located in the region nt 296–302, which contains a series of three tandem repeats (GAGAGAG). In addition, as in 66% of all affected unrelated families (12 of 18) the same molecular defect, involving a deletion of 2 bp, namely AG or GA, within this region has been identified, it is suggested that this region is likely to represent a mutational hot spot. This hypothesis is underlined by the fact that such repeats, like classical microsatellite loci, are prone to mutations by slipped strand mispairing.
Further, in the 28 unrelated normal controls screened for
PROP1 gene polymorphisms, none of the 56 chromosomes
analyzed presented any alteration of the PROP1 gene as
reported in the affected patients. Polymorphisms were found in these
normal controls as detailed in Table 3, but appear to be without
functional impact, at least as far as CPHD is concerned.
Although the PROP1 gene seems to be an important candidate gene for CPHD, the reason for the disorder remains unknown in many of the patients. As most of our understanding of pituitary development has come from rodent animal studies, it is likely that more information on the characterization of CPHD will be derived from the recent studies of CPHD phenotypes in mice generated by targeted disruption of other pituitary-specific transcription factors (27, 28, 29, 30, 31, 32). There are recent data on the Hesx-1 gene causing forebrain midline defects with pituitary dysplasia in Hesx-1 null mutant mice as well as septo-optic dysplasia in patients identified as having a Hesx-1 mutation (33). Such animal models adapted and applied to human studies will contribute to define more and more genetic factors involved in pituitary development.
In conclusion, we report six different PROP1 gene alterations that were found among 35 patients suffering from CPHD derived from 18 unrelated families. All but 1 mutation were located in the PROP1 gene encoding the homeodomain, which plays a major role in transcriptional regulation. Furthermore, three tandem repeats of the dinucleotide GA at the location nt 296–302 appear to represent a hot spot for combined pituitary hormone deficiency. Although the PROP1 gene seems to be an important candidate gene for CPHD, further studies are needed to evaluate other genetic defects involved in pituitary development. Phenotypes of murine strains generated by targeted disruption of pituitary transcription factors might help to further elucidate the mechanisms resulting in CPHD in humans.
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Footnotes |
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Received December 3, 1998.
Revised February 4, 1999.
Accepted February 8, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cys at codon 120 (R120C). J Clin Endocrinol
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