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Original Studies |
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (G.A., V.B.), 226014 Lucknow, India; and Murdoch Childrens Research Institute, Royal Children’s Hospital (S.C., P.Q.T.), Parkville, 3052 Victoria, Australia
Address all correspondence and requests for reprints to: Dr. Paul Thomas, Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Victoria, Australia. E-mail: thomasp{at}cryptic.rch.unimelb.edu.au
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Abrogation of the program controlling pituitary cell differentiation in humans can result in combined pituitary hormone deficiency (CPHD), a disorder in which multiple AP hormones are deficient. This condition is mainly sporadic in occurrence (3), but familial forms have also been described with autosomal recessive, autosomal dominant, and X-linked recessive modes of inheritance (4, 5, 6). Identification of genes responsible for CPHD has resulted from molecular genetic analysis of two nonallelic spontaneous mutant mouse strains. Snell dwarf mice, which harbor a mutation in the Pit-1 homeobox gene, display AP hypoplasia resulting from the lack of thyrotroph, somatotroph, and lactotroph differentiation (7, 8). Mutations in the orthologous human gene, POUF1, have been identified in CPHD patients with a parallel phenotype (reviewed in Ref. 9). More recently, the genetic basis of the Ames dwarf (df) mutant mouse strain was shown to be a missense mutation in the Prop1 homeobox gene (10). In addition to a severe lack of thyrotrophs, somatotrophs, and lactotrophs, (df/df) mice have reduced gonadotropin levels, indicating that gonadotroph differentiation is compromised (11, 12). Several studies have shown that PROP1 mutations in humans are associated with CPHD in patients who display gonadotropin, GH, TSH, and PRL deficiencies (13 ; reviewed in Ref. 9). To date, at least seven different mutations have been described, most of which are located within the homeodomain, which contains the DNA-binding activity of the PROP1 gene product. Of these, the most common is the 301–302AGdel allele, which may represent approximately 50% of all mutations (14).
Here we describe a novel PROP1 mutation in a large consanguineous Indian family in which three homozygous individuals are affected with CPHD. An unusual feature of two of the affected subjects in this family is that their CPHD phenotype includes severe cortisol deficiency. This phenotypic feature has been detected previously in only two CPHD families (15, 16), both of which contain the common 301–302delAG mutation. Our study provides additional evidence for the existence of ACTH/cortisol deficiency in PROP1 homozygotes and supports a role for PROP1 in the differentiation and/or maintenance of corticotroph cells in the mature AP.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Informed consent was obtained from all subjects for all DNA and endocrine testing performed for the study. The study was approved by the institutional ethics committee. GH was tested by an insulin tolerance test (insulin dose, 0.1 U/kg) in patients IV.2 and IV.1 and a clonidine test (150 µg/m2) in patient IV.4. GH was assayed by a monoclonal immunoradiometric assay (IRMA;(Diagnostics Systems Laboratories, Inc., Webster, TX) with intra- and interassay coefficients of variation (CVs) of 3.1% and 5.9%, respectively, and a sensitivity of 0.01 µg/L. A peak value below 5 µg/L was regarded as diagnostic of GH deficiency. LH and FSH were tested after GnRH (100 µg) stimulation. The test was performed after stopping testosterone replacement for 6 weeks. Both hormones were measured by IRMAs (Diagnostic Products, Los Angeles, CA). For LH, the intra- and interassay CVs were 1.0% and 2.2%, respectively, and sensitivity was 0.15 U/L, whereas for FSH, these parameters were 2.2%, 4.0%, and 0.06 U/L, respectively. Plasma ACTH was sampled with due precautions at 0800 h for patients IV.1 and IV.2, in the case of the former after stopping glucocorticoid replacement for 4 weeks. ACTH was measured by an IRMA (DiaSorin, Inc., Stillwater, MN), with intra- and interassay CVs of 2.5% and 3.2% and a sensitivity of 0.3 pmol/L. Cortisol was estimated at baseline and after insulin hypoglycemia in patients IV.1 and IV.2, and 60 min after 250 µg Cosyntropin in patients IV.1 and IV.4. A peak value more than 497 nmol/L was regarded as normal. PRL was tested in a pooled sample of three equal volumes of blood taken 20 min apart. It was measured by IRMA (Diagnostic Products), and the intra- and interassay CVs and sensitivity were 1.1%, 1.6%, and 0.1 µg/L. Testosterone and T4 were measured in a basal sample by RIA, and TSH was measured by IRMA (Diagnostic Products). The intra- and interassay CVs and sensitivity were 5.0%, 6.0%, and 0.1 nmol/L for testosterone; 2.7%, 4.2%, and 3.3 nmol/L for T4; and 2.5%, 5.1%, and 0.03 mU/L for TSH.
PROP1 mutation detection
Genomic DNA was extracted from ethylenediamine tetraacetate
blood samples using standard procedures. A 387-bp product incorporating
the entire exon 2 sequence was amplified by PCR using 2F and 2R primers
(2F, 5'-AAAGACTGGAGCAGCACAGGACGCA; 2R, 5'-CTGCATTTCTTTCCTGAGA). PCR
conditions were 95 C for 3.5 min, 95 C for 30 s, 57 C for 30
s, and 72 C for 30 s for 35 cycles, then 72 C for 5 min. For
sequencing, PCR products were gel purified, and approximately 50 ng
template were sequenced using the 2F primer and the Thermo Sequenase
Terminator Cycle Sequencing Kit incorporating
[
-33P]dideoxy-NTPs (U.S. Biochemical Corp., Cleveland, OH). Sequencing products were separated on a
6.5% denaturing polyacrylamide gel and detected using
Kodak BioMax MR film (Eastman Kodak Co.,
Rochester, NY). Genotype analysis was performed by XhoI
restriction digestion of approximately 300 ng gel purified 2F/2R PCR
product. Digestion products were separated on a 3% NuSieve agarose
gel.
D5S408 marker analysis
Fifty nanograms of genomic DNA were PCR amplified with
D5S408 oligonucleotide primers (D5S408F, 5'-ACAACTTCCAACCCTGAGAT;
D5S408R, 5'-ACTGTGCCTAGCCTTCATTT) incorporating
[-33P]deoxy-ATP using the following cycle
profile: 94 C for 3 min, 94 C for 30 s, 55 C for 30 s, and 72
C for 30 s for 32 cycles, then 72 C for 10 min. Reaction products
were separated on a denaturing 6.5% polyacrylamide gel and visualized
by exposure to Kodak BioMax MR film.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patient IV.1. Patient IV.1 had presented to another
institution at age 13 yr, with the complaint of growth retardation of
8-yr duration. Parental consanguinity was present (first cousins, Fig. 1
). Investigation reports (Table 1) and prescriptions available with the
patient suggested that the treating endocrinologist had diagnosed
central hypothyroidism with GH deficiency. Cortisol production during
insulin hypoglycemia was recorded to be normal, and serum testosterone
was prepubertal. The patient was receiving regular thyroid hormone
replacement after this time and intermittent GH therapy. Testosterone
replacement was started at age 17 yr.
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). Prednisolone in a dose of 5 µg/day was added to his treatment
regimen of testosterone and T4. In 1999, his
endocrine evaluation was repeated. An insulin tolerance test carried
out after stopping prednisolone for 4 weeks revealed both GH and ACTH
deficiencies (Table 1). The basal ACTH value of 6 pmol/L confirmed that
the low cortisol response was not due to suppression of corticotrophs
by prednisolone therapy. A GnRH stimulation test conducted after
stopping testosterone replacement for 6 weeks yielded undetectable LH
and FSH values. Testosterone was undetectable in this basal sample.
Serum PRL was 2.4 µg/L. Twenty-four-hour urine output was normal. No
imaging of the sella was performed. Patient IV.2
Patient IV.2, the younger brother of IV.1 (Fig. 1), presented
initially to another institution at the age of 9 yr with the complaint
of growth retardation. Only the details of cortisol levels during an
insulin tolerance test conducted at that time are available (Table 1),
but the diagnosis was recorded as GH deficiency with central
hypothyroidism and normal cortisol production. After this time, he
received regular T4 replacement and intermittent
GH therapy. At the age of 19 yr, he underwent TRH and GnRH stimulation
tests at another institution (Table 1), the results of which suggest
hypogonadotropic hypogonadism with a normal basal PRL but subnormal
response to TRH. Records of TSH values with TRH stimulation were not
available. Testosterone treatment was started at age 19 yr. He had also
received hCG treatment for 9 months before presenting to our hospital
at age 25 yr. He was 142 cm tall (-4.8 standard deviations on Indian
reference charts) with a lower segment of 74 cm and an arm span of
144.5 cm. He displayed mild frontal bossing. He was fully androgenized,
but with low testicular volumes of 4 mL bilaterally. He was clinically
euthyroid. Fundus examination was normal. In 1999, at age 26 yr, he
underwent another insulin tolerance test. Cortisol production was
normal (Table 1) and GH was deficient. A GnRH test, performed after
stopping testosterone for 6 weeks, showed undetectable LH and FSH and
testosterone values. PRL was 5.6 µg/L.
Patient IV.4
Patient IV.4, a first cousin of IV.1 and IV.2 (Fig. 1), presented
to our hospital in 1995, at age 10 yr, for the complaint of growth
retardation of 5 yr duration. He was proportionately short statured,
with height SD score of -3.7 according to Indian growth
references. He had mild frontal bossing, chubby cheeks, and a high
pitched voice. His ankle jerks showed a slow relaxation. Fundus
examination did not show optic atrophy. His bone age on a previous
x-ray taken at 7 yr of age corresponded to 3 yr (17). A
clinical diagnosis of central hypothyroidism with GH deficiency was
made. After central hypothyroidism was confirmed biochemically and
treated, GH deficiency and ACTH deficiency were diagnosed by clonidine
and short ACTH tests, respectively (Table 1). Thyroid hormone and
cortisol replacement brought on myoclonic epilepsy, which was not
previously present. A subsequent prolonged period of noncompliance with
hormone replacements caused the epilepsy to abate, only to be
precipitated again in 1999 when he was restarted on
T4 in gradually increasing doses from 25–75
µg/day. Euthyroidism as well as seizures came with a daily dose of 75
µg. He could not afford GH therapy. In 1999, at age 14 yr, he
continued to be prepubertal. A computed tomography scan, performed
before his presentation to us, showed the presence of an empty sella.
PRL was 5.2 µg/L.
PROP1 mutation analysis
The presence of CPHD with hypogonadism in subjects IV.1, IV.2, and
IV.4, who are members of a large consanguineous Indian pedigree (Fig. 1), prompted us to scan for a mutation in the PROP1 gene.
Our analysis focused on exon 2, as most mutations, including the common
296delAG allele, are found in this exon (14). Sequence
analysis of an exon 2 product amplified from affected individual IV.1
revealed a homozygous 13-bp deletion spanning nucleotides 112–124
(Fig. 2A). This deletion leads to
a frame shift after 37 amino acids of the open reading frame, resulting
in a premature stop codon at position 480 (Fig. 3). As the frame shift occurs upstream of
the homeodomain and C-terminal activation domain, this mutation is
expected to generate a null allele.
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) to genotype available
family members. This analysis showed that all three affected
individuals are homozygous for the mutation, and that their parents are
heterozygotes (Fig. 2B and data not shown). These data indicate that
homozygosity for the 112–124del PROP1 deletion results in
CPHD in this family and that this disorder, as has been demonstrated
previously, has a recessive mode of inheritance (9). Origin of the 112–124del mutation
The presence of the 112–124del allele in subjects III.6, III.7, and III.11 (all of whom are parents of affected children) in this consanguineous pedigree reflects the inheritance of the deletion from a common ancestor (possibly I.1 or I.2). However, as III.12 is also a carrier of this mutation (confirmed by sequencing; data not shown), but was not aware of being related to her husband’s family, it is not clear whether the 112–124del mutation has arisen independently in her or whether she is, in fact, distantly related to her husband. To address this issue, we used the polymorphic dinucleotide repeat marker D5S408, which is closely linked to PROP1 (18) to determine whether the 112–124del mutation is segregating with a single D5S408 allele. The two affected brothers, IV.1 and IV.2, are both homozygous for the D5S408 3 allele. This indicates that the 112–124del mutation is cosegregating with the D5S408 3 allele on this side of the pedigree. In contrast, their first cousin, IV.4, is heterozygous for the 3 and 6 D5S408 alleles. His heterozygous father III.11, has passed on the mutation with the 3 allele, which is consistent with his brother, III.7, carrying the mutation on the 3 allele. III.12 is heterozygous for the 3 and 6 D5S408 alleles and, in contrast to her husband’s family, has passed the mutation to her affected son, IV.4, on the same chromosome as the D5S408 6 allele. It is therefore possible that an independent mutation event generating the 112–124del deletion has occurred in III.12 or her ancestors.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have presented AP hormone secretion data for three patients who are
homozygous for the 112–124del mutation. One of these patients (IV2)
has the classical CPHD phenotype incorporating GH, TSH, FSH/LH, and
borderline PRL deficiencies with a normal cortisol response to an
insulin tolerance test (ITT; Table 1). In contrast, affected
individuals IV.1 and IV.4 display significant cortisol
deficiency. This unusual phenotypic feature has also been reported in a
15-yr-old girl who is homozygous for the 301–302AG deletion
(15) and more recently in the five of the six patients,
aged 43 yr or above, in a large inbred Brazilian kindred with the same
mutation (16). The 15-yr-old girl had been previously
tested at age 6.6 yr and at that time displayed a normal response to
ITT, indicating that her cortisol deficiency is progressive. We
observed a similar phenotype in subject IV.1. At 13 yr of age he had a
normal cortisol response to an ITT, but by age 30 yr showed cortisol
deficiency in both insulin tolerance and ACTH tests. It is also
interesting to note the reduced basal cortisol and PRL levels in
subject IV.2 at age 26 yr compared with those at age 9 and 19 yr,
respectively. This is consistent with previous reports of evolving
pituitary deficiencies with increasing age (14, 19).
The basis for phenotypic variation between individuals who are homozygous for a mutation of PROP1 is not clear. The presence of normal corticotroph levels in df/df mice (8) and normal cortisol levels in most CPHD patients (9) argues that PROP1 is not necessary for corticotroph differentiation during pituitary development. However, as there is evidence from rat studies that differentiated cells within the AP cells undergo constant renewal (20), it is possible that PROP1 is required for maintenance of the corticotroph population in the mature pituitary. This hypothesis provides an explanation for the progressive nature of the cortisol deficiency seen in the patient reported by Mendonca et al. (15) as well as in our patient IV.1 and raises the possibility that cortisol deficiency may develop in other PROP1 homozygotes. It is interesting to note that GH, TSH, and gonadotropin deficiencies are known to progress with age in CPHD patients with PROP1 mutations (14), indicating that PROP1 may also be necessary for renewal of these cell types in the mature pituitary. Such a role for the PROP1 gene product may also explain the expression of PROP1 in normal human pituitary tissue (21). Regardless of the underlying mechanism, it is clear that phenotypes associated with PROP1 deficiency are variable and in the most severe form are manifest as panhypopituitarism, including cortisol deficiency. From a clinical perspective, such variation should be taken into consideration when considering the possibility of PROP1 mutation in new patients with CPHD.
Although the family that we have studied is consanguineous, the existence of a common ancestor for all carriers of the mutation was not apparent. To investigate the possibility that the 112–124del mutation event had occurred on more than one occasion, we compared segregation of the PROP1 mutation with the closely linked polymorphic marker D5S408. As the mutation cosegregated with both the 3 (III.6, III.7, and III.11) and the 6 (III.12) D5S408 alleles, it is possible that independent mutation events giving rise to the same mutation may have occurred. Recurrent mutation has been shown to occur with the 301–302AG deletion, which occurs in approximately 50% of familial CPHD families (18). However, given that the 112–124del mutation has not been identified previously, and that the mutation has only been detected in Indians, it is possible that III.11 and III.12 share a common ancestor and that a recombination event between the mutation and the D5S408 marker has resulted in segregation of the mutation on distinct haplotypes.
Although PROP1 mutations account for a significant proportion of CPHD families, the genetic basis for many cases remains obscure. Although other pituitary homeodomain transcription factors associated with congenital CPHD, such as POUF1 and HESX1/RPX (22), may account for some of these cases, additional disease genes remain to be identified. Given the functional conservation of PROP1, Pit1/POUF1, and HESX1 in mice and humans (9), it seems likely that functional analysis of murine pituitary genes, particularly through the generation of mouse mutants, will lead to the identification of human pituitary disease genes. No doubt, functional studies identifying the PROP1 binding partners and target genes will also provide CPHD candidate genes.
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Acknowledgments |
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Footnotes |
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Received March 21, 2000.
Revised July 31, 2000.
Accepted August 4, 2000.
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References |
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Cys at codon 120 (R120C). J Clin Endocrinol
Metab. 83:3727–3734.This article has been cited by other articles:
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