Division of Endocrinology and Metabolism, Department of Medicine The Johns Hopkins University School of Medicine Baltimore, Maryland 21205; Section of Endocrinology, Department of Medicine, Washington Hospital Center and Medlantic Research Institute, Washington, CD 20010
Address correspondence and requests for reprints to: Michael A. Levine, M.D., Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Ross Building, Room 863, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: mlevine{at}jhu.edu
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Introduction |
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In human thyroid, activation of the TSH-Re leads to stimulation of
adenylyl cyclase and ß-isoforms of phospholipase C (PLC-ß) via
coupling of the receptor to Gs and members of the
G/11 family, respectively (5, 6). Activation of these
signaling pathways leads to the production of second messengers
(e.g. cAMP, inositol phosphate, diacyl glycerol, and
intracellular calcium) that together promote thyroid cell growth,
proliferation, and function. Recognition of the critical role of
thyrotropin in initiating and sustaining these signals led to the
hypothesis that genetic defects in the TSH-Re might produce significant
and tissue-specific phenotypic consequences. These predictions have now
been fulfilled in a series of elegant observations (7, 8). First,
somatic and germline mutations in the TSH-Re gene that result in
constitutive (i.e. ligand independent) activation of the
receptor have been found in many toxic thyroid adenomas (9, 10) and in
occasional patients with nonimmune hyperthyroidism (11, 12, 13),
respectively. Second, TSH-Re gene mutations that inactivate the
receptor have been associated with inherited hypothyroidism in both
humans (8, 14, 15) and mice (16) with TSH resistance. The thyroid
dysfunction produced by these contrasting mutations in the TSH-Re joins
a growing list of endocrine and metabolic disorders that have been
ascribed to mutations in genes encoding other G-protein coupled
heptahelical receptors, including but not limited to activating and
inactivating mutations of the calcium sensing receptor and the FSH
receptor, activating mutations of the LH receptor and the PTH/PTHrP
receptor, and inactivating mutations of the type 2 vasopressin
receptor. These findings have suggested that altered receptor function,
once considered to be an unusual basis for endocrine dysfunction, may
in fact be a common cause of tissue-specific pathology.
With this premise in mind, it was logical for Xie and coworkers to target the TSH-Re gene for analysis in the three families with isolated resistance to TSH reported in this issue of JCEM (17) (see page 3933). It was therefore no doubt surprising, if not disappointing, to the authors that they were unable to detect mutations in the TSH-Re gene in any of these three families. Moreover, using intragenic polymorphic markers to perform linkage analysis, they were able to exclude the TSH-Re gene as a candidate in two of the families. These results should not have been totally unexpected, however. The affected subjects in two of these kindreds demonstrated a dominant mode of transmission of TSH resistance, whereas autosomal recessive mode of inheritance has been found in previously described patients with TSH-Re gene mutations (8). Although the development of TSH resistance, albeit mild, in the affected subjects in these two kindreds could have been explained by a novel dominant negative mutation of the TSH-Re, the phenotype is also consistent with a defect in some other tissue specific component of the signaling cascade.
These results confirm and extend a similar negative report by Ahlbo
et al. (18) published elsewhere earlier this year. Together,
these two negative studies lend further support to the notion that most
genetic disorders display genetic heterogeneity, that is, similar
phenotypes (i.e. phenocopies) can arise from defects in
different genes. Despite the fact that both of these studies (17, 18)
report essentially "negative" results, they nevertheless represent
highly significant contributions. First, they remind us that receptor
mutations may not account for all forms of hormone resistance, and
second, they oblige us to consider how defects in other components of
the signaling cascade might impair hormone action. It was no doubt this
latter consideration that led Xie et al. (17) to study both
an upstream signal (the ß subunit of thyrotropin) as well as a
downstream target (the subunit of Gs) of the TSH-Re. These analyses
also failed to disclose gene mutations or biological abnormalities that
could account for TSH resistance in these unusual patients.
These results invite comparison to another syndrome of hormone
resistance, pseudohypoparathyroidism (PHP; reviewed in ref. 19). PTH
resistance is the hallmark of PHP, a syndrome described by Fuller
Albright in 1942 as the first example of a human disorder in which
endocrine deficiency resulted not from a lack of hormone but from
failure of target tissues to respond appropriately to the hormone (20).
The subsequent observation that intravenous administration of PTH to
normal subjects stimulates a marked increase in the urinary excretion
of nephrogenous cAMP led to the development of PTH infusion protocols
that have enabled distinction between the several variants of PHP.
Thus, patients with PHP type 1 fail to show either a phosphaturic or a
nephrogenous cAMP response after administration of exogenous PTH (21).
By contrast, patients with the far more uncommon type 2 variant of PHP
fail to show a phosphaturic response to PTH but manifest a normal
nephrogenous cAMP response (22). These findings implicate defects in
the G protein-coupled PTH receptor-adenylyl cyclase signaling cascade
as the basis for PTH resistance in patients PHP type 1 and suggest that
more distal defects must account for apparent hormone resistance in
patients with PHP type 2. This hypothesis has been confirmed in
patients with PHP type 1a, in whom hormone resistance is accompanied by
an unusual constellation of developmental defects that are collectively
termed Albrights hereditary osteodystrophy. This autosomal dominant
disorder is characterized by an approximately 50% deficiency of Gs
activity, which arises as a consequence of mutations of the Gs gene
that reduce function or expression of the Gs
protein (19). Patients
with PHP type 1a have decreased responsiveness not only to PTH, but to
other hormones as well, including TSH, whose receptors are coupled by
Gs to activation of adenylyl cyclase. Although generalized deficiency
of Gs
likely accounts for multiple hormone resistance, the
relationship of the Gs
defect to Albrights hereditary
osteodystrophy remains uncertain. Patients with a second autosomal
dominant form of PTH resistance, PHP type 1b, lack features of
Albrights hereditary osteodystrophy, have normal levels of Gs
protein, and manifest target tissue resistance only to PTH. These
features are certainly consistent with a defect in PTH receptor action,
but nucleotide sequence analysis of the gene (23, 24) and cDNA (25)
encoding the type 1 PTH-receptor (also termed the PTH/PTHrP-receptor),
as well as linkage analysis using intragenic polymorphisms (26), have
excluded this candidate gene as the basis for PHP type 1b. Thus, the
primary genetic defect(s) in this disorder remains as great a mystery
as the cause of TSH resistance in the three kindreds described in this
issue of JCEM (17).
When the notorious criminal Willie Sutton (19011980) was once asked why he robbed banks, Sutton is reputed to have replied, "Because thats where the money is." This apocryphal parable has long inspired investigators to seek straightforward explanations for their observations and to examine first the most obvious candidates. So what are the molecular defects that cause TSH resistance in these three kindreds and PTH resistance in patients with PHP type 1b, now that "Suttons law" has apparently led us to where the money "aint?" With normal genes encoding the TSH-Re and PTH-Re, what are the appropriate next steps in defining the molecular basis for these disorders? What other genes can be proposed as likely, or even potential, candidates, to thereby justify the arduous (if not tedious) efforts necessary to accomplish a comprehensive evaluation? The answers to these questions are many, and we invite the readers to consider the possibilities. Certainly other G proteins, receptor kinases, isoforms of adenylyl cyclase or phosphodiesterase, as well as protein kinases and their tissue specific substrates are all attractive possibilities. We will not review here all the possible gene defects that may impair TSH action in the patients described by Xie et al. (17), but we will suggest that speculation is made all the more difficult by our lack of knowledge concerning the ability of their thyroid glands to generate cAMP in response to TSH.
An alternative to the candidate gene approach is to perform whole genome linkage analysis to identify genes that are tightly linked to the disorder. This method is highly ambitious; one must analyze a large number of chromosomal markers that are distributed throughout the genome using DNA samples from affected and nonaffected members of large, multigenerational families. To be successful, one needs a sufficiently large number of subjects to ensure that a convincing statistical odds of linkage (LOD) score can be achieved. This approach assumes that the same gene, albeit not the same mutation, is defective in all the families. For TSH resistance, the clinical variability may create significant problems, as inclusion of even one misidentified family can invalidate or obscure linkage.
We eagerly look forward to studies that advance our understanding of the molecular pathogenesis of hormone resistance disorders. The negative studies of TSH resistance and PHP type 1b provide timely reminders that looking "where the money is" might not always be straightforward: while the money is likely to be in the bank, it may not always be kept within the vault.
Received October 14, 1997.
Accepted October 14, 1997.
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References |
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