Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia.
OBJECTIVE
High myopia is one of the leading causes of blindness worldwide, with high heritability. However, only a few causative genes have been identified, and the pathogenesis is still unclear. Our aim was to identify a novel causative gene in a family with autosomal-dominant, nonsyndromic high myopia.


METHODS
Whole-genome linkage and whole-exome sequencing were conducted on the family. Real-time quantitative polymerase chain reaction and immunoblotting were applied to test the functional consequence of the candidate mutation. Sanger sequencing was performed to screen for the candidate gene in other families or sporadic cases.


RESULTS
A heterozygous missense mutation, c.871G>A (p.Glu291Lys), within P4HA2 was cosegregating with the phenotype in the family. The segregating mutation caused premature degradation of unstable messenger RNA. Subsequent screening for P4HA2 in 186 cases identified an additional four mutations in 5 cases, including the frameshift mutation c.1349_1350delGT (p.Arg451Glyfs*8), the nonsense mutation c.1327A>G (p.Lys443*), and two deleterious missense mutations, c.419A>G (p.Gln140Arg) and c.448A>G (p.Ile150Val). The missense mutation c.419A>G (p.Gln140Arg) was recurrently identified in a sporadic case and was segregating in a three-generation family.


CONCLUSIONS
P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. This study also indicated that the disruption of posttranslational modifications of collagen is an important factor in the pathogenesis of high myopia.
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Hui
H
Guo
Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.
Ping
P
Tong
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Yanling
Y
Liu
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Lu
L
Xia
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Tianyun
T
Wang
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Qi
Q
Tian
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Ying
Y
Li
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Yiqiao
Y
Hu
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Yu
Y
Zheng
Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Xuemin
X
Jin
1] The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China [2] Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.
Yunping
Y
Li
Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.
Wei
W
Xiong
The Xiangya Hospital, Central South University, Changsha, China.
Beisha
B
Tang
The Xiangya Hospital, Central South University, Changsha, China.
Yong
Y
Feng
1] The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China [2] College of Life Science and Technology, Xinjiang University, Xinjiang, China.
Jiada
J
Li
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Qian
Q
Pan
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Zhengmao
Z
Hu
1] The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China [2] College of Life Science and Technology, Xinjiang University, Xinjiang, China [3] Key Laboratory of Medical Information Research, Central South University, Changsha, China.
Kun
K
Xia
D059472:Exome / Q000235:genetics; D005799:Genes, Dominant; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D009216:Myopia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D064828:Prolyl Hydroxylases / Q000235:genetics*
C000591164:P4HA2 protein, human; D064828:Prolyl Hydroxylases