We report on a father and daughter with
hand-foot-genital syndrome (HFGS) with typical skeletal and genitourinary anomalies due to a 14-residue
polyalanine expansion in HOXA13. This is the largest (32 residues)
polyalanine tract so far described for any
polyalanine mutant protein.
Polyalanine expansion results in
protein misfolding, cytoplasmic aggregation and degradation; however, HOXA13
polyalanine expansions appear to act as loss of function mutations in contrast to gain of function for HOXD13
polyalanine expansions. To address this paradox we examined the cellular consequences of
polyalanine expansions on
HOXA13 protein using COS cell transfection and immunocytochemistry. HOXA13
polyalanine expansion
proteins form cytoplasmic aggregates, and distribution between cytoplasmic aggregates or the nucleus is
polyalanine tract size-dependent.
Geldanamycin, an Hsp90 inhibitor, reduces the steady-state abundance of all
polyalanine-expanded
proteins in transfected cells. We also found that wild-type HOXA13 or HOXD13
proteins are sequestered in HOXA13
polyalanine expansion cytoplasmic aggregates. Thus, the difference between HOXA13
polyalanine expansion loss-of-function and HOXD13
polyalanine expansion dominant-negative effect is not the ability to aggregate wild-type group 13 paralogs but perhaps to variation in activities associated with refolding, aggregation or degradation of the
proteins.