Polyalanine expansions in human

Abstract

Beside the well-known polyglutamine expansions involved in several neurodegenerative disorders, convergent recent findings pointed to the expansion of polyalanine stretches as a disease mechanism in congenital malformations, skeletal dysplasia and nervous system anomalies. Polyalanine stretches have been predicted in roughly 500 human proteins among which nine have been ascribed to disease phenotype by expansion of polyalanines. The function of polyalanine stretches is largely unknown. This paper aims to review the rapidly growing evidences for a disease-causing mechanism common to expansion of homopolymeric tracts whatever the amino acid involved is.

A human mutation in Phox2b causes lack of CO 2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

“…Moreover, our mouse mutants will enable us to study the developmental history of the demise of the RTN/ pFRG neurons and the reason for their vulnerability. In fact, the reasons for the selective vulnerability of some neuronal types and the resistance of others that also express the mutant protein are not understood for any of the polyAla expansion disorders (36,37). Finally, because heterozygous Phox2b-null mutants have only a mild and transient breathing defect (38), the results at hand demonstrate already that the respiratory failure of Phox2b 27Ala/ϩ mutants and by extrapolation of CCHS patients is caused by a toxic gain of function or a dominant-negative effect, not by haploinsufficiency.…”

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

“…Polyalanine tracts are found in the homeodomain of many transcription factors, 27 and have been shown to be associated with several human disorders. 28 Current evidence suggests that polyalanine tracts function by changing the normal folding, degradation and cytoplasmic aggregation of the mutant proteins. 28 Both alanine repeats and the flanking amino acids are conserved, suggesting that both are important to the function of the polyalanine tract.…”

“…28 Current evidence suggests that polyalanine tracts function by changing the normal folding, degradation and cytoplasmic aggregation of the mutant proteins. 28 Both alanine repeats and the flanking amino acids are conserved, suggesting that both are important to the function of the polyalanine tract. 28 Furthermore, the alanine at position 34 is highly conserved and located inside the polyalanine tract (29-AAAATAAA-36) (Figure 1).…”

“…28 Both alanine repeats and the flanking amino acids are conserved, suggesting that both are important to the function of the polyalanine tract. 28 Furthermore, the alanine at position 34 is highly conserved and located inside the polyalanine tract (29-AAAATAAA-36) (Figure 1). Similar to M37, its conservation also extends back to the amphibians.…”

Sensitive Detection of Polyalanine Expansions in PHOX2B by Polymerase Chain Reaction Using Bisulfite-Converted DNA

“…14,15 Polyalanine expansions of PHOX2B, which transcriptionally controls neuronal differentiation, generate CCHS via dysfunction of the autonomic nervous system. 16 For that reason, the mutated variants need to be detected precisely.…”