A novel start codon mutation of the MERTK gene in a patient with retinitis pigmentosa.
OBJECTIVE
Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy.


METHODS
To identify the defective gene, whole exome sequencing was performed. Candidate causative variants were selected and validated using Sanger sequencing. Segregation analysis of the causative gene was performed in additional family members. To verify that the mutation has an effect on protein synthesis, an expression vector containing the first ten amino acids of the mutant protein fused with the DsRed2 fluorescent protein was constructed and transfected into HEK293T cells. Expression of the fusion protein in the transfected cells was measured using fluorescence microscopy.


RESULTS
By filtering against public variant databases, a novel homozygous missense mutation (c.3G>A) localized in the start codon of the MERTK gene was detected as a potentially pathogenic mutation for autosomal recessive RP. The c.3G>A mutation cosegregated with the disease phenotype in the family. No expression of the first ten amino acids of the MerTK mutant fused with the DsRed2 fluorescent protein was detected in HEK293T cells, indicating that the mutation affects the translation initiation site of the gene that may lead to loss of function of the MerTK signaling pathway.


CONCLUSIONS
We report a novel missense mutation (c.3G>A, p.0?) in the MERTK gene that causes severe vision impairment in a patient. Taken together with previous reports, our results expand the spectrum of MERTK mutations and extend our understanding of the role of the MerTK protein in the pathogenesis of retinitis pigmentosa.
Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Worapoj
W
Jinda
Clinical Molecular Pathology Laboratory, Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Naravat
N
Poungvarin
Laboratory for Integrated Bioinformatics, Core for Precise Measuring and Modeling, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
Todd D
TD
Taylor
Department of Medical Genome Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
Yutaka
Y
Suzuki
Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Wanna
W
Thongnoppakhun
Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Chanin
C
Limwongse
Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Patcharee
P
Lertrit
Bioinformatics and Data Management for Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Prapat
P
Suriyaphol
Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
La-Ongsri
LO
Atchaneeyasakul
D000328:Adult; D018387:Codon, Initiator / Q000235:genetics*; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005451:Fluorescein Angiography; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D041623:Tomography, Optical Coherence; D014162:Transfection; D000076202:c-Mer Tyrosine Kinase
D018387:Codon, Initiator; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase