18.03.16 Polyalanine repeat disorders Flashcards Preview

Modes of inheritance > 18.03.16 Polyalanine repeat disorders > Flashcards

Flashcards in 18.03.16 Polyalanine repeat disorders Deck (17):

Which codons encode alanine?

1. GCU
2. GCC
3. GCA
4. GCG


Where are polyalanine tracts commonly found? What is the result of mutation here?

Transcription factors (except PABPN1), usually outside of recognised protein domains.

Result of mutation = congenital malformation syndromes


Give some features of polyalanine tract expansions.

Critical threshold ~19 at which point poplypeptides aggregate and form intracellular inclusions.

Usually meiotically and mitotically stable, probably due to imperfect nucleotide sequences.

High de novo frequency

Expanded polyalanine repeats are thought to destabilize the native conformation of the protein and alter protein levels and activity.

Protein dysfunction following polyalanine expansion has been reported to cause transcriptional dysregulation which may delay early developmental processes or induce cytotoxicity in polyalanine disease models.


How many disorders have been associated with polyalanine repeat expansions?



What is the potential effect of polyalanine expansions on protein dysfunction?

Polyalanine tract expansion beyond a certain threshold induces protein misfolding leading to aberrant protein interactions, protein degradation, mislocalization and/or aggregation which can result in a gain of function, complete to partial loss-of-function, or a dominant negative effect.

These functional alterations may influence the normal transcriptional activity and compromise essential cellular functions, or may lead to cell death in specific tissues, contributing eventually to the development of polyalanine disorders.


Give three examples of polyalanine repeat disorders.

1. Synpolydactyly type II (SPD)
2. Hand–foot–genital syndrome (HFGS)
3. Holoprosencephaly (HPE)
4. X linked mental retardation (XLMR)
5. Oculopharyngeal muscular dystrophy (OPMD)


Where is the polyalanine repeat expansion associated with synpolydactyly type II? What are the clinical features?

Autosomal dominant

HOXD13 (2q31.1) exon 1 expansion (15A-22/29A)

Phenotype: limb and GU-tract malformation

HOXD13 encodes a homeobox transcription factor of the D cluster required for regulation of limb and genital patterning during development. Expression of expanded HOXD13 (expHOXD13) induces the formation of cytoplasmic aggregates that sequester the wild-type HOXD13 (wtHOXD13), which is normally localized to the nucleus. The expHOXD13 nuclear mislocalization and the entrapment of the wtHOXD13 in protein aggregates may render both proteins inactive and is in agreement with a dominant negative mechanism.


Where is the polyalanine repeat expansion associated with Hand–foot–genital syndrome (HFGS)? What are the clinical features?


HOXA13 (7p15.2) Exon 1

Phenotype: affects the distal limbs and the genitourinary (GU) tract.

Missense and nonsense mutations, deletions, in-frame insertion and polyalanine expansions in HOXA13 gene (7p15.2) have been previously described in HFGS. HOXA13 is a homeobox transcription factor of the A cluster, required for limb and genital patterning. Expansions have been reported in three different polyalanine tracts (Table 1) within exon 1 of HOXA13.


Where is the polyalanine repeat expansion associated with holoproscencephaly (HPE)? What are the clinical features?

Mutations including deletions, insertions and polyalanine expansions in exon 3 of ZIC2 (13q32.3) are found in ∼3 to 4% of HPE cases. Partial LoF

Central nervous system developmental disorder that presents with the failure of the proper formation of midline structures of the brain.

Mutations in several genes result in HPE, including SHH (HPE3), ZIC2 (HPE5), SIX3 (HPE2) and TG interacting factor (TGIF) (HPE4).


Where is the polyalanine repeat expansion associated with X-linked mental retardation? What are the clinical features?

ARX (Xp21.3) exon 2

Expansions in two of the four alanine tracts of the ARX gene have been described in families with non-syndromic XLMR and X-linked infantile spasm syndrome (West syndrome) and Partington syndrome (mental retardation and dystonic movements of the hands).

ARX belongs to the paired type homeobox genes. Loss of function mutations in ARX are associated with a more severe condition than polyalanine repeat expansions: X-linked lissencephaly with abnormal genitalia.

The difference in phenotypes suggests that the polyalanine repeat expansion does not result in loss of function (toxic gain of function suggested in table 1). When expanded, the ARX protein remains in the nucleus and induces protein aggregation and cellular toxicity in vitro.


Where is the polyalanine repeat expansion associated with Oculopharyngeal muscular dystrophy (OPMD) ? What are the clinical features?

Usually AD, late-onset degenerative disorder

Symptoms usually begin between the fourth and sixth decade of life and primarily involve eyelid drooping (ptosis), difficulty swallowing (dysphagia) and proximal limb weakness.

OPMD is caused by expansions of a poly alanine tract in exon 1 of the PABPN1 gene (14Q11.2).

Normal alleles consist of 10 alanine codons.
Mutations consist of short expansions of +1 to +7 in the alanine tract. +1 alanine gives recessive OPMD, +2 to +7 alanines gives dominant OPMD.
A point mutation at c.35G>C, p.(Gly12Ala), can also cause OPMD as it substitutes ala in the 11th repeat position which is followed by a further 2 ala codons, so effectively causes a +3 ala expansion leading to dominant OPMD (Robinson et al 2006).

PABPN1 encodes a nuclear poly(A)-binding protein, which is highly expressed in skeletal muscle, and the protein shuttles between the nucleus and the cytoplasm.


Where is the polyalanine repeat expansion associated with Congenital central hypoventilation syndrome ? What are the clinical features?

AD. PHOX2B (4p13)

Abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep.

These patients typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia


What is the likely molecular basis on polyalanine expansions?

Unequal crossing-over


What are some of the differences between polyglutamine and polyalanine expansions?

Polyglutamine tracts:
1. usually larger in size and often encoded by perfect CAG repeat tracts.
2. more likely to expand than polyalanine tracts which are smaller in size and usually encoded by interrupted triplet repeats.
3. Meiotically and mitotically unstable.


What is some evidence behind unequal crossing over being the mechanism with polyalanine repeat expansions?

Consistent with an unequal crossing-over mechanism for polyalanine expansions is the finding of predicted polyalanine contraction products of recombination in control populations.


What is the link between polyalanine repeat expansion and B-sheet formation?

Protein aggregation seems to be a characteristic feature of polyalanine expansions.

In vitro, polyalanine peptides containing 7 to 15 alanines undergo variable levels of conformational transition from a monomeric α-helix to a macromolecular β-sheet.

Those peptides harbouring a number of alanines greater than 15 are completely converted from monomer to β-sheet.

In vivo, expanded polyalanine tracts may show a propensity to form β-sheet complexes that may promote stronger protein–protein interactions leading to elevated levels of dense, insoluble protein assemblies.


What are the possible cell death mechanisms in polyalanine diseases?

1. When polyalanine proteins aggregate, they become dysfunctional.
2. Protein aggregates can recruit essential cellular components and compromise their function, which may cause a toxic gain of-function.
3. Elongation of polyalanine tracts may lead to protein mislocalization without necessarily involving protein aggregation, or induce the protein to aberrantly interact with DNA target sites and/or critical cellular factors, altering mechanisms essential for cellular homeostasis