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U N I T 1
Cell and Tissue Function
(“happy puppet”) syndrome, which exhibits mental
retardation along with paroxysms of laughter, ataxia,
and seizures. In contrast, when the same deletion is
inherited from the father, Prader-Willi syndrome results,
and the child manifests intellectual impairment, uncon-
trolled appetite, obesity, and diabetes.
Figure 6-6 is a pedigree showing another inheritance
pattern typical of genetic imprinting. In the example
shown, gene expression is entirely “turned off” during
spermatogenesis, so that any offspring who inherit the
affected allele from the father will merely be carriers.
Expression is “turned on” during oogenesis, however, so
those who inherit the allele from the mother will express
the disorder.
Triplet Repeat Mutations: Fragile X Syndrome
Fragile X syndrome is the prototype of disorders in
which the mutation is characterized by a long repeat-
ing sequence of three nucleotides.
1–3
Thus far, about
40 diseases associated with neurodegenerative changes,
including Huntington disease and myotonic dystrophy,
have been classified as triplet repeat mutations, in which
the expansion of specific sets of three nucleotides within
a gene disrupts its function.
Fragile X syndrome
, an abnormality in the X chro-
mosome, is the common cause of inherited intellectual
disability.
2,16–19
It is second only to Down syndrome as
an identifiable cause of intellectual impairment. Because
the syndrome is an X-linked disorder, it is more preva-
lent in males (1 in 4000) than females (1 in 8000).
19
In addition to intellectual disability, the fragile X syn-
drome is characterized by distinctive features including
a large face, a large mandible, and large, everted ears.
Hyperextensible joints, a high-arched palate, and mitral
valve prolapse, which are observed in some cases, mimic
a connective tissue disorder. Some physical abnormali-
ties may be subtle or absent. The most distinctive fea-
ture, which is present in 90% of prepubertal boys, is
macroorchidism, or large testes. Because girls have two
X chromosomes, they are more likely to have relatively
normal cognitive development, or they may show a
learning disability in a particular area, such as math-
ematics. Women with the disorder may also experience
premature ovarian failure or begin menopause earlier
than women who are not affected by fragile X syndrome.
The term
fragile X
stems from the cytogenic observa-
tion of a constriction or fragile site on the long arm of
the X chromosome. The fragile X syndrome results from
a mutation in the
FMR1
(fragile X mental retardation 1)
gene that has been mapped to this fragile site.
2,3
The pro-
tein product of the FMR1 gene, the
fragile X mental
retardation protein
(FMRP), is a widely expressed ribo-
nucleic acid (RNA)-binding protein. The protein trav-
els from the cytoplasm to the nucleus, where it binds
specific messenger RNAs (mRNAs) and then transports
them from the nucleus to the synaptic ends of axons and
dendrites, where the FMRP–mRNA complexes perform
critical roles in regulating the translation of mRNA.
3
The inheritance of the FMR1 gene follows the pat-
tern of X-linked traits, with the father passing the gene
on to all his daughters but not his sons. However, unlike
other X-linked recessive disorders, approximately 20%
of males who have been shown to carry the fragile X
mutation are clinically and cytogenetically normal.
These “carrier males” can transmit the disease to their
grandsons through their phenotypically normal daugh-
ters. Another peculiarity is the presence of mental retar-
dation in approximately 50% of carrier females. Both
of these peculiarities have been related to the dynamic
Affected individuals
Have the mutant allele but are not affected
Do not have the mutant allele and are not affected
Generation I
Generation II
Generation III
+
+
+
+
+
+
+
+
+
+
+
+
A
B
C
D
FIGURE 6-6.
Pedigree of genetic
imprinting. In generation I, male
(A)
has
inherited a mutant allele from his affected
mother (not shown); the gene is “turned
off” during spermatogenesis, and therefore
none of his offspring (generation II) will
express the mutant allele, regardless of
whether they are carriers. However, the
gene will be “turned on” again during
oogenesis in any of his daughters
(B)
who
inherit the allele. All offspring (generation
III) who inherit the mutant allele will be
affected. All offspring of normal children
(C)
will produce normal offspring. Children
of female
(D)
will all express the mutation if
they inherit the allele.
