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Original Studies |
Gene and Chromosome 2q371
The First Department of Medicine (H.S., T.S., S.O., K.N.), Wakayama University of Medical Science, Wakayama 640, Japan; and Departments of Cellular and Molecular Pharmacology and Medicine (T.I.), and Cardiovascular Research Institute, University of California, San Francisco, California 94143-0450
Address all correspondence and requests for reprints to: Dr. Hidenobu Sakaguchi, The First Department of Medicine, Wakayama University of Medical Science, 27 Nanaban-cho, Wakayama 640, Japan. E-mail: nishihos{at}naxnet.or.jp
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Abstract |
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-subunit of Gs (Gs), the stimulatory
regulator of adenylyl cyclase. Some sporadic cases occur in which
patients with phenotype similar to AHO have a deletion of chromosome
2q37. However, in this patient, both the Gs gene structure and the
biological activity were normal. In addition, chromosome analysis
revealed a normal pattern with no visible deletion of chromosome 2q37.
Our findings suggest that one or more other factors may be involved in
the pathogenesis of AHO-related disease. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, the subunit of Gs, the stimulatory
regulator of adenylyl cyclase. A number of Gs mutations were found
in AHO patients (2, 3, 4, 5, 6, 7, 8, 9). AHO is usually associated with resistance to
PTH and some other hormones whose receptors are coupled to Gs
[pseudohypoparathyroidism type-Ia (PHP-Ia)]. The AHO phenotype alone
that appears in a family of PHP-Ia is termed
pseudopseudohypoparathyroidism. Some sporadic cases occur in which patients with AHO-like phenotype have a small terminal deletion of chromosome 2 [Del(2)q37] (10, 11). These patients do have brachydactyly and mental retardation but lack renal PTH resistance and sc calcification.
Here, we report a sporadic case of AHO-like syndrome complicated by several hormonal disorders.
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Subjects and Methods |
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The patient is a 37-yr-old woman who is short (height 147 cm)
and obese (wt, 68 kg) and has a round face, a short neck, marked
shortening of both fifth metacarpals (Fig. 1
), and mental retardation. However, she
has no evidence of ectopic sc calcification. She presented as
normocalcemic; and her serum levels of intact PTH, urinary cAMP
excretion, and tubular reabsorption of phosphate all were within
the normal range. She had no PTH resistance in the kidney, as indicated
by the Ellsworth-Howard test (Table 1B).
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). Her
glucose disposal rate, by the hyperinsulinemic-euglycemic glucose clamp
test, was low, indicating that she had severe insulin resistance. Her
metabolic control for diabetes improved with diet therapy. Her case was further complicated by central diabetes insipidus (DI). She had poly- and hyposthenuria. Her plasma osmolality was slightly high; nevertheless, her serum arginine-vasopressin level was low. A hypertonic saline stimulating test showed central DI pattern. Moreover, the signal intensity on T1-weighted magnetic resonance imaging of neurohypophyshysis was not detected.
In addition, several other hormonal abnormalities were present
(Table 1). Her plasma GH and somatomedin C were low. Her
plasma GH responses to both GHRH and arginine were low. Her basal
plasma glucagon, ACTH, and cortisol levels were slightly higher than
normal; but from other clinical examinations, it is unlikely that she
had a glucagonoma or Cushing’s disease/syndrome. She did not have a
pituitary adenoma. Her thyroid and gonadal functions were normal. She
had first menstruation at the age of 13, and thereafter she had
irregular menses and was sterile. Computed tomography scanning and
ultrasonographic study revealed no evidence of the organized disease in
her uterus and ovaries, but she neglected to undergo the other
gynecological check-ups.
Her parents and siblings were normal in height and weight and did not have AHO or any hormonal disorders.
Methods
To try to diagnose and identify the pathogenesis, we checked the
genetic defects associated with the two likely diseases. Specifically,
to check AHO, we looked for a mutation and low activity of Gs. To
check AHO-like phenotype, we looked for deletion of chromosome
2q37.
Sequencing determination of Gs
Genomic DNA was extracted from peripheral leukocytes by the
standard method (12). The Gs mutations were identified both by a
solid-phase PCR-direct sequence method and by the sequencing of the
amplified DNA fragments subcloned into the plasmid. To amplify exon
2–13, including each bordering intron region of Gs gene, the
primers described previously (13) were used. For the PCR to amplify
exon 1, two primers were used (5'-ATGGGCTGCCTCGGGAACAG-3', and
5'-TTACCCAGCAGCAGCAGGCG-3').
Measurement of the biological activity of Gs
The biological activity of Gs was determined with a
complementation assay based on the ability of solubilized extracts of
erythrocyte membranes prepared from S49 cyc(-) murine lymphoma cells,
which genetically lack Gs protein (14). As the control for this
assay, blood cells extracted from three healthy normal subjects were
used.
Analysis of chromosomal and microsatellite marker within 2q37
Chromosomal analysis on peripheral lymphocytes was performed by the standard method, in Shionogi Biomedical Laboratory (Osaka, Japan). Typing of three polymorphic markers (D2S395, D2S140, and D2S125) (15), located within the important regions of chromosome 2q37, were also analyzed for this patient and her parents (10).
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Results |
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gene in this patient. For exon 1,
we also did not find any mutations in the DNA fragment from 20 bp
downstream of the initiation codon to the region of the donor site of
intron 1. We were not able to perform PCR for the other DNA fragment of
exon 1, possibly because guanine and cytosine were rich in these
bordering regions.
The Gs bioactivity of this patient was normal. [103 ± 19%
(n = 3) of the average of the three normal subjects]
The chromosomes of the patient were 46, XX normal female karyotype,
with no visible deletion on 2q on metaphase spreads (Fig. 2). Her alleles were all heterogeneous,
one from her mother and other from her father.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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deficiency. However, the patient does not have PTH resistance, sc
calcification, or any family history that is especially consistent with
AHO-like phenotype. A definite diagnosis is not possible because the
genetic defects causing AHO or AHO-like phenotype are not present:
specifically, the patient did not have Gs defect or Del(2)q37.
Although most patients with AHO have reduced bioactivity of
Gs, because of a gene mutation (2, 3, 4, 5, 6, 7, 8, 9), our case seems to have normal
gene structure and bioactivity of Gs. However, it should be noted
that we were unable to examine a part of exon 1 for a mutation. An
instructive mutation (R231H) of the Gs was reported (9), in which
reduced bioactivity could not be detected using the erythrocyte Gs
assay (qualitative defect). Thus, it is still possible that a mutation
in the unexamined part of exon 1 results in a qualitative Gs
defect.
It was reported that Del(2)q37 is important in the pathogenesis of AHO-like phenotype or brachydactyly (10, 11). These cases, which occur sporadically, involve subjects who have mental retardation but lack PTH resistance and sc calcification. Clinically, our patient may belong to this category. Although our patient did not have gross Del(2)q37, she may have a small rearrangement or a point mutation in the (as yet unidentified) relevant gene in this region.
The present case was complicated by several endocrinopathies:
non-insulin-dependent diabetes mellitus, central DI, and GH deficiency.
However, the first two seem to be unrelated to AHO or AHO-like
phenotype. Insulin resistance and hyposecretion of ADH are not
associated with Gs defect. Even though we did not find a Gs defect,
the third one (the GH deficiency) may be related to a Gs defect,
because the GHRH receptor couples to Gs and, in fact, the conditions of
some patients with PHP-Ia are complicated by GH deficiency (16). In
addition, a case of AHO-like phenotype with Del(2)q37 was complicated
with the low secretion of GH (10), suggesting a possible causal
relation.
Thus, genetics in the pathogenesis of AHO-related diseases is
still complicated. One or more other factors, in addition to the Gs
gene mutation and the rearrangement of chromosome 2q37, may be
involved. Identification of the genetic defect will contribute to our
understanding of the hormone action and the pathogenesis of AHO-related
diseases.
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Acknowledgments |
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Footnotes |
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2 Present address (T.I.) is Fourth Department of Internal Medicine,
University of Tokyo School of Medicine, 3-28-6 Mejirodai, Bunkyo-ku,
Tokyo 112, Japan.
Received September 30, 1997.
Revised January 15, 1998.
Accepted January 22, 1998.
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References |
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gene mutations in Albright gs hereditary
osteodystrophy. J Med Genet. 31:835–839. in patients with gain and loss of endocrine
function. Nature. 371:164–168.[CrossRef][Medline]
mutant in a patient with Albright hereditary
osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J Biol Chem. 269:25387–25391. gene. Hum Genet. 97:73–75.[Medline]
mutant. Proc Natl Acad Sci USA. 94:5656–5661. gene. Proc Natl Acad
Sci USA. 85:2081–2085.This article has been cited by other articles:
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  G. Mantovani, R. Romoli, G. Weber, V. Brunelli, E. De Menis, S. Beccio, P. Beck-Peccoz, and A. Spada Mutational Analysis of GNAS1 in Patients with Pseudohypoparathyroidism: Identification of Two Novel Mutations J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4243 - 4248. [Abstract] [Full Text]
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