Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

Abstract

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

• Authors: Beryl Royer-Bertrand, Silvia Castillo-Taucher, Rodrigo Moreno-Salinas, Tae-Joon Cho, Jong-Hee Chae, Murim Choi, Ok-Hwa Kim, Esra Dikoglu, Belinda Campos-Xavier, Enrico Girardi, Giulio Superti-Furga, Luisa Bonafé, Carlo Rivolta, Sheila Unger, Andrea Superti-Furga
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 17154 (Nov 24 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26598328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HSP70 Heat-Shock Proteins
• HSPA9 protein, human
• Mitochondrial Proteins

Topics

• Abnormalities, Multiple (diagnostic imaging, genetics)
• Bone Diseases, Developmental (diagnostic imaging, genetics)
• Child, Preschool
• DNA Mutational Analysis
• Female
• Genetic Association Studies
• HSP70 Heat-Shock Proteins (genetics)
• Humans
• Mitochondrial Proteins (genetics)
• Musculoskeletal Abnormalities (diagnostic imaging, genetics)
• Mutation, Missense
• Radiography
• Syndrome