Mutation in SSUH2 Causes Autosomal-Dominant Dentin Dysplasia Type I.
Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Fu
F
Xiong
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Zhisong
Z
Ji
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.|Department of Prenatal Diagnosis Center, Maternal and Child Health Hospital, Dongguan, China.
Yanhui
Y
Liu
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Yu
Y
Zhang
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Lingling
L
Hu
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Qi
Q
Yang
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Qinwei
Q
Qiu
Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Lingfeng
L
Zhao
School of Stomatology, Zhengzhou University, Zhengzhou, China.
Dong
D
Chen
Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Zhihui
Z
Tian
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Xuan
X
Shang
Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Leitao
L
Zhang
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Xiaofeng
X
Wei
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cuixian
C
Liu
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Qiuxia
Q
Yu
Department of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Meichao
M
Zhang
Center for Medical Genetics, Southwest Hospital, Third Military Medical University, Chongqing, China.
Jing
J
Cheng
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Jun
J
Xiong
Department of Forensic Science, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Dongri
D
Li
Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Xiuhua
X
Wu
Center for Medical Genetics, Southwest Hospital, Third Military Medical University, Chongqing, China.
Huijun
H
Yuan
Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Wenqing
W
Zhang
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Xiangmin
X
Xu
D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D003805:Dentin Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D005799:Genes, Dominant; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D055815:Young Adult; D015027:Zebrafish
D018832:Molecular Chaperones; C550238:SSUH2 protein, human
DDI; SSUH2; dentin dysplasia type I; mouse; odontogenesis; zebrafish