Trends in Genetics
Alanine tracts: the expanding story of human illness and trinucleotide repeats
Section snippets
Synpolydactyly (syndactyly type II)
Syndactyly type II (SPD) is a rare, dominantly inherited limb malformation syndrome, in which affected individuals exhibit a combination of syndactyly (fused digits) and polydactyly (excess digits). Several other digital anomalies can also occur, and the severity of malformation is variable both within and between families [2].
The demonstration that expansions of a 15-residue alanine tract in the N-terminus of the HOXD13 gene co-segregate with SPD, established HOXD13 as the causative gene for
Cleidocranial dysplasia
Cleidocranial dysplasia (CCD) is a dominantly inherited condition in which there are persistently open sutures in the skull, absent or hypoplastic clavicles, dental anomalies, short stature and a variety of minor skeletal anomalies. In 1997, the defective gene was identified as RUNX2 (formerly CBFA1) [12], a member of the Runt class of transcription factors with a role in osteoblast differentiation. Targeted inactivation of one allele of the Runx2 (Cbfa1) gene in the mouse is sufficient to
Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy (OPMD) is a progressive, late onset, dominantly inherited disorder where the main features are drooping of the eyelid, difficulty in swallowing and proximal limb-muscle weakness. Positional cloning led to the discovery that the poly-adenine binding protein nuclear-1 (PABPN1) causes OPMD. PABPN1 is an ubiquitously expressed protein that binds nascent poly-adenine tails of pre-mRNAs, both promoting their formation and controlling their length [15], and
Holoprosencephaly
Holoproseccephaly (HPE) is a severe developmental malformation in which there is failure of formation of midline structures in the embryonic forebrain [26]. A small percentage of cases have been shown to be caused by mutations in single genes, for example, ZIC2. The ZICs are a family of zinc finger transcription factor genes defined by their homology to the Drosophila melanogaster gene odd-paired (opa) [27]. Positional cloning demonstrated that heterozygous loss-of-function mutations in ZIC2
Hand-foot-genital syndrome
Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited disorder characterized by small thumbs and short great toes, fusion of the carpals and tarsals and a variety of genitourinary abnormalities, including hypospadias in males, and abnormalities of Müllerian duct fusion, such as bicornuate uterus and septate vagina, in females.
Mutations in HOXA13 result in HFGS and a total of 10 families with HOXA13 mutations have now been reported 31, 32, 33, 34. Of these, four have nonsense
Blepharophimosis, ptosis and epicanthus inversus
Blepharophimosis, ptosis and epicanthus inversus (BPES) is a dominant syndrome in which affected individuals have characteristic facial features including abnormal eyelids. Premature ovarian failure (POF) is a common but inconsistent feature of the syndrome in women.
Positional cloning identified FOXL2 (Forkhead box like2), a transcription factor with a 14 residue C-terminal alanine tract, as the causative gene in this disorder. Of the 30 families with BPES and FOXL2 mutations described to date,
X-linked mental retardation
Sex determining region Y-box 3 (SOX3) is a transcription factor, expressed in the brain, with a role in neural development and is so named because of its homology with sex determining region Y (SRY). A screen for mutations in families with X-linked mental retardation (MRX) mapped to Xq26-q27 (where SOX3 is located) yielded a single large family in which mental retardation (MR), short stature and growth hormone deficiency segregated with an 11 alanine expansion of the 15 residue tract normally
Syndromic and non-syndromic X-linked mental retardation
The ARX gene (Aristaless related homeobox) contains a homeodomain related to that present in the Drosophila gene, aristaless (al) [40], which is a paired class homeodomain protein with multiple functions in the fly [41]. On the basis of its position at Xp22.13 and its expression in fetal brain, ARX has been considered as a candidate gene for MRX. Two groups have reported that expansions of two different alanine tracts in the ARX gene result in both non-syndromic MRX and several syndromic
Congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome (CCHS) is a usually sporadic disorder of autonomic nervous system development, which leads to an abnormal ventilatory response to hypercarbia and hypoxemia and occasionally other autonomic abnormalities, such as Hirschprung disease. Because of its role in autonomic nervous system development in mice [50], PHOX2B was considered to be a candidate gene for this disorder and, indeed, 18 out of 29 individuals with CCHS were shown to have mutations in PHOX2B
Comparison of poly-Q and poly-A expansions
Of the nine genes described previously, eight are transcription factors that function during development, and mutations in them – including alanine tract expansions – result in abnormalities of the body plan. The organs affected differ in each case but the basic idea of disturbed development is similar. Presumably, a mutation, whether it results in the gain of a dominant negative activity as in HOXD13 or a loss-of-function, results in altered expression of downstream target genes, and this, in
Alanine tract function
An analysis of 10 000 human genes showed that 20% have at least one homopolymer tract [52]. Of these, 16% are poly-A, resulting in a total of ∼300 poly-alanine containing genes. Given the frequency with which homopolymer tracts in general and poly-A tracts in particular are found in transcription factors, it is intriguing to consider what role poly-A tracts might have in transcription factor function.
Several authors have suggested that the alanine rich regions of transcription factors are
Mutational mechanism
Another contrast between the poly-Q and poly-A tracts is that Q-tracts tend to be polymorphic whereas A-tracts are not. Related to this, expanded poly-Q tracts (CAG or CTG triplet repeats) tend to be meiotically and somatically unstable whereas expanded poly-A tracts are generally stable. Normal poly-Q tracts can contain >40 repeats, whereas poly-A tracts do not generally exceed 20. Pathologically expanded poly-Q tracts can be large, whereas the largest pathologic poly-A tracts seem to be <30.
Conclusion
Expansions of alanine tracts are a recent and growing addition to the list of disease-causing mutations. At present, there is little understanding of what the normal functions of alanine tracts are, although given the frequency with which they are found in transcription factors and can result in complete or partial loss-of-function and a dominant negative gain-of-function, it seems likely that alanine tracts will turn out to have interesting roles. The future is likely to bring more examples of
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