title: Spag17 deficiency results in skeletal malformations and bone abnormalities.
abstract: Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro-CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild-type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild-type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts.
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Teves
authors.affiliation: Department of Radiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Gobalakrishnan
authors.initials: G
authors.lastname: Sundaresan
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cohen
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hyzy
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Illya
authors.initials: I
authors.lastname: Kajan
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Maczis
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Costanzo
authors.affiliation: Department of Radiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Jamal
authors.initials: J
authors.lastname: Zweit
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000002:abnormalities* / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D002923:Cilia / Q000473:pathology; D005260:Female; D005269:Femur / Q000002:abnormalities; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008868:Microtubule Proteins / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D012886:Skull / Q000503:physiopathology; D013977:Tibia / Q000002:abnormalities
chemical_list: D008868:Microtubule Proteins; C000607333:SPAG17 protein, mouse