Curation HFG HOXA13-I

Gene HOXA13

Disease HFG-I

Inheritance AD

Score

0 + 3.5 = 3.5 / 18

Genetic + experimental = total

Classification

Limited

Refuted

Moderate

Definitive

Last Updated 08/18/2025

Pubs Reviewed 2

Publication Span 3.08 years

Publication Interval 3.08 years

Curator(s) Macayla Weiner, Laurel Hiatt, Elbay Aliyev

Description

This HFG-I HOXA13 curation is based on experimental evidence from PMID 17935235 and primary mouse-model evidence from PMID 15385446. PMID 17935235 reports a father and daughter with hand-foot-genital syndrome carrying a heterozygous +14 alanine expansion in HOXA13 polyalanine tract III and shows, in COS-7 cells, length-dependent cytoplasmic aggregation of HOXA13 polyalanine expansion proteins, altered steady-state abundance after geldanamycin treatment, and sequestration of wild-type HOXA13/HOXD13. PMID 15385446 reports human HOXA13 polyalanine expansions in all three large tracts and a Hoxa13Ala28 knock-in mouse model with a +10 alanine expansion in tract III, showing a Hoxa13 loss-of-function-like phenotype with normal RNA expression/splicing but reduced steady-state HOXA13 protein abundance. Evidence is primarily experimental and supports a loss-of-function mechanism through post-transcriptional reduction/degradation of expanded HOXA13 protein. Note that there are three reported pathogenic polyalanine tracts in HOXA13 and only PMID 17935235 was able to be directly tied to this specific tract.

All criTRia Curations Locus Page

Genetic evidence

Total: 0

No genetic evidence details available.

Experimental evidence

Total: 3.5

Per page

Category	Type	Citation	Score	Details
Function	Biochemical function	PMID:17935235 PMID:15385446	0.5	HOXA13 polyalanine expansion proteins showed misfolding/cytoplasmic aggregation and reduced steady-state protein abundance; mouse Hoxa13Ala28 data showed normal RNA expression/splicing but reduced HOXA13 protein abundance, supporting post-transcriptional protein loss.
Function	Protein interaction	PMID:17935235	0.5	Co-expression assays showed polyalanine-expanded HOXA13 sequestered wild-type HOXA13 and wild-type HOXD13 proteins into cytoplasmic aggregates; this is locus-relevant protein interaction evidence from non-patient cell assays.
Function	Regulatory impact	PMID:17935235 PMID:15385446	0	No evidence of regulatory impact. Western blot and immunohistochemistry data showed reduced steady-state HOXA13 protein abundance for the expanded allele despite normal RNA expression and splicing, indicating post-transcriptional protein reduction rather than altered transcription, epigenetic regulation, or splicing.
Functional Alteration	Non-patient cells	PMID:17935235	0.5	COS-7 transfection/immunocytochemistry assays showed wild-type HOXA13 localized to the nucleus, while +10 and +14 HOXA13 polyalanine expansion proteins formed cytoplasmic aggregates, with greater aggregation for longer expansions.
Models	Non-human model organism	PMID:15385446	2	Mouse Hoxa13Ala28 knock-in model with a +10 alanine expansion in polyalanine tract III showed a phenotype indistinguishable from Hoxa13 null mice. Mutant limb buds had normal Hoxa13 RNA expression and splicing but reduced steady-state HOXA13 protein by immunohistochemistry and Western blot, supporting loss of function through in vivo degradation of the expanded protein.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.