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A 6-month-old infant is evaluated for growth retardation. The pediatrician notes signs
suggestive of deficiency of a peptide hormone. On further questioning, the pediatrician learns
that one of seven siblings died in childhood with a similar clinical picture. A first cousin of the
patient also exhibited this syndrome. Both parents, however, are apparently healthy. The
pediatrician believes that an autosomal recessive genetic disorder causes this infant's
apparent hormone deficiency state. The pediatrician uses knowledge of general endocrine
pathways to investigate the possible causes.

1. 1. What three basic defects can you envision that would lead to the infant's hormone
deficiency state?
2. 2. For each of these basic defects, what specific factors could be involved in this
hormonal genetic disorder?
3. 3. How could you measure plasma or target cell samples to determine the precise
endocrine lesion in this patient?
4. 4. What molecular biologic investigations would be required to prove your final diagnosis
and to provide the basis for genetic counseling?
5. 5. Why don't all the siblings exhibit the biologic defect?


1. The apparent loss of action of a peptide hormone in this patient could result from:
a. An inability to secrete an adequate amount of the peptide hormone in question.
b. A loss of recognition of the hormone signal by the target cells of the hormone.
c. A loss of the signal transduction mechanism that ultimately stimulates the intracellular
action of the hormone.

2. Inability to secrete a peptide hormone could be the consequence of a number of possible

defects. The endocrine cell may have lost its ability to recognize the stimulus for the
secretion of the stored peptide hormone. An example would be a deficiency in the enzyme
glucokinase, which is required for the recognition of elevated plasma glucose levels as a
stimulus for the secretion of insulin by pancreatic islet beta cells. Another defect could lie
in the gene for synthesis of the hormone that could have a nonsense or missense
mutation in the hormone sequence. A nonsense mutation would lead to complete loss of
production of any authentic hormone molecules. A missense mutation would lead to
production of a hormone sequence, the structure of which might be altered enough to
decrease the biologic activity of the hormone. The primary transcript of the hormone
gene, that is, the preprohormone, could be mutated in an area that is critical for
processing the preprohormone to the hormone. If so, the hormone molecule might not be
cleaved normally from its precursor nor released to act on its target cells. An example
would be a mutated pro insulin molecule or preproparathyroid hormone molecule.

Peptide hormones act through plasma membrane receptors with various domains. A gene
mutation could give rise to various types of abnormalities in the hormone receptor. If the
extracellular portion of the receptor were abnormal, binding of the hormone would be
deficient because of a low affinity to the receptor. If a transmembrane loop of the receptor
were abnormal, it might not interact properly with an adjacent signal transducer molecule.
If the intracellular tail of the receptor were abnormal, an ATP binding site or tyrosine

kinase active site could be abnormal and fail to carry out the hormone's action. Because
receptor molecules also arise from a proreceptor, a processing error could occur that
would yield a total receptor deficiency.

Another genetic error that could lead to defective hormone action would be in
transcription of a mutant G-protein. Such a mutant G-protein could fail to activate second
messenger pathways such as adenylyl cyclase-cAMP.

Finally, a genetic error could lead to reduced synthesis of an enzyme that was a key
element in the ultimate intracellular action of a hormone.

3. If deficient synthesis of the hormone were the problem, basal plasma levels of the hormone
measured by radioimmunoassay would be low. Furthermore, the plasma hormone level
would not rise in response to normal physiologic stimulation. If authentic hormone were
administered to the patient, a normal response should occur.

On the other hand, if an abnormal hormone molecule were being synthesized and
released, plasma levels might well be elevated, as measured by radioimmunoassay. This is
because an assay antibody might still recognize portions of the abnormal molecule, and
negative feedback from lack of hormone action would stimulate hormone secretions.
However, if plasma hormone levels were measured by a biologic assay, the plasma levels
would be low. If authentic hormone were administered in this situation, the patient still
should respond normally. If processing of a preprohormone were defective, plasma levels
of the preprohormone would be elevated, whereas plasma levels of the hormone itself
would be low.

In all situations where the defect in hormone action lies at the receptor step, plasma levels
of the hormone should be very high because of negative feedback. If a preparation of the
patient's receptor from available cells, such as white blood cells, were reacted with
radioactively labeled hormone in vitro, the response curve would be shifted to the right;
such a shift indicates a receptor with decreased affinity. If authentic hormone were
administered to the patient, the physiologic response would be less than normal.

In situations where the block in hormone action was downstream from the receptor step,
plasma hormone levels again should be high. However, preparations of the patient's
receptor would bind radioactively labeled hormone molecules normally in vitro. On the
other hand, preparations of target cells from the patient would fail to exhibit either
increases in second messenger levels (e.g., cAMP hormone) or normal increases in
metabolic products of hormone action (e.g., glycogen), when incubated with the hormone.

4.After studies of the type just mentioned, the likely site of biologic hormone deficiency
should be pinpointed. The appropriate gene (hormone, receptor, G-protein, or target
enzyme) should be cloned from the patient and its structure compared with that of the
normal gene. The same genes from the two parents and all siblings should be cloned.
Because the inheritance pattern appears to be autosomal recessive, each parent would be
expected to have one normal allele for the gene in question and one abnormal allele like
that of the patient. The patient should have two abnormal alleles. Any sibling with one
mutant allele would be identified as a carrier for this defect in hormone action and suitably
counseled when at a reproductive age.

5. In an autosomal recessive disease, one-fourth of the siblings will have two normal alleles
(one from each parent) for the gene in question and hence will be disease free. Siblings
with only one mutant allele are like the parents. The presence of one normal allele is
enough to direct sufficient synthesis of the normal hormone, receptor, or G-protein to
allow for a normal biologic state with only 50% of the normal concentration. This would
imply that the mutant gene product does not inhibit the action of the normal gene product
(as is the case in some instances