Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome

Utsch, Boris; McCabe, Colleen D; Galbraith, Kenneth; Gonzalez, Ricardo; Born, Mark; Dötsch, Jörg; Ludwig, Michael; Reutter, Heiko; Innis, Jeffrey W (2007). Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome. American journal of medical genetics. Part A, 143A(24), pp. 3161-8. Hoboken, N.J.: Wiley-Liss 10.1002/ajmg.a.31967

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
UniBE Contributor:	Utsch, Boris
ISSN:	1552-4825
ISBN:	17935235
Publisher:	Wiley-Liss
Language:	English
Submitter:	Anette van Dorland
Date Deposited:	04 Oct 2013 14:55
Last Modified:	05 Dec 2022 14:17
Publisher DOI:	10.1002/ajmg.a.31967
PubMed ID:	17935235
Web of Science ID:	000251405100038
URI:	https://boris.unibe.ch/id/eprint/23452 (FactScience: 41877)