The Mouse Hoxd13spdh Mutation, a Polyalanine Expansion Similar to Human Type II Synpolydactyly (SPD), Disrupts the Function but Not the Expression of Other Hoxd Genes

• DOI: 10.1006/dbio.2001.0382
• Publication Date: 2002-09-16T15:45:48Z
• Authors: Sylvia Bruneau; Kenneth R. Johnson; Masakazu Yamamoto; Atsushi Kuroiwa; Denis Duboule
• Keywords: 0301 basic medicine; Time Factors; 590; In-Situ-Hybridization; Peptides/chemistry; Homeodomain-Proteins; Gene-Expression-Regulation-Developmental; Mice; ddc:590; SUPPORT-U-S-GOVT-P-H-S; Forelimb; Medicine and Health Sciences; Developmental; Genetic-Complementation-Test; In Situ Hybridization; Genes, Dominant; Genes-Dominant; Homozygote; Life Sciences; Gene Expression Regulation, Developmental; Phenotype; Bone-and-Bones; Human; Transcription-Factors; Genotype; Bone and Bones; Polydactyly/genetics; 03 medical and health sciences; Animals; Humans; Dominant; SUPPORT-NON-U-S-GOVT; Molecular Biology; Alleles; Homeodomain Proteins; Animal; Forelimb/pathology; info:eu-repo/classification/ddc/590; Genetic Complementation Test; Time-Factors; Cell Biology; Transcription Factors/biosynthesis/genetics; Polydactyly; Bone and Bones/abnormalities; Gene Expression Regulation; Genes; Mutation; Peptides; Homeodomain Proteins/biosynthesis/genetics/physiology; Developmental Biology; Transcription Factors

Polyalanine expansion in the human HOXD13 gene induces synpolydactyly (SPD), an inherited congenital limb malformation. A mouse model was isolated, which showed a spontaneous alanine expansion due to a 21-bp duplication at the corresponding place in the mouse gene. This mutation (synpolydactyly homolog, spdh), when homozygous, causes malformations in mice similar to those seen in affected human patients. We have studied the genetics of this condition, by using several engineered Hoxd alleles, as well as by looking at the expression of Hox and other marker genes. We show that the mutated SPDH protein induces a gain-of-function phenotype, likely by behaving as a dominant negative over other Hox genes. The mutation, however, seems to act independently from Hoxa13 and doesn't appear to affect Hox gene expression, except for a slight reduction of the HOXD13 protein itself. Developmental studies indicate that the morphological effect is mostly due to a severe retardation in the growth and ossification of the bony elements, in agreement with a general impairment in the function of posterior Hoxd genes.