Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis.
Retinitis pigmentosa (RP) is a highly heterogeneous group of disorders characterized by degeneration of the retinal photoreceptor cells and progressive loss of vision. While hundreds of mutations in more than 100 genes have been reported to cause RP, discovering the causative mutations in many patients remains a significant challenge. Exome sequencing in an individual affected with non-syndromic RP revealed two plausibly disease-causing variants in TRNT1, a gene encoding a nucleotidyltransferase critical for tRNA processing. A total of 727 additional unrelated individuals with molecularly uncharacterized RP were completely screened for TRNT1 coding sequence variants, and a second family was identified with two members who exhibited a phenotype that was remarkably similar to the index patient. Inactivating mutations in TRNT1 have been previously shown to cause a severe congenital syndrome of sideroblastic anemia, B-cell immunodeficiency, recurrent fevers and developmental delay (SIFD). Complete blood counts of all three of our patients revealed red blood cell microcytosis and anisocytosis with only mild anemia. Characterization of TRNT1 in patient-derived cell lines revealed reduced but detectable TRNT1 protein, consistent with partial function. Suppression of trnt1 expression in zebrafish recapitulated several features of the human SIFD syndrome, including anemia and sensory organ defects. When levels of trnt1 were titrated, visual dysfunction was found in the absence of other phenotypes. The visual defects in the trnt1-knockdown zebrafish were ameliorated by the addition of exogenous human TRNT1 RNA. Our findings indicate that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina.
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Adam P
AP
DeLuca
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
S Scott
SS
Whitmore
Department of Biology.
Jenna
J
Barnes
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Tasneem P
TP
Sharma
Department of Biology.
Trudi A
TA
Westfall
Department of Biology.
C Anthony
CA
Scott
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Matthew C
MC
Weed
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Jill S
JS
Wiley
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Luke A
LA
Wiley
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Rebecca M
RM
Johnston
The Stephen A. Wynn Institute for Vision Research, Department of Biomedical Engineering, Department of Biochemistry, and.
Michael J
MJ
Schnieders
Department of Internal Medicine; The University of Iowa, Iowa City, IA, USA.
Steven R
SR
Lentz
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Budd A
BA
Tucker
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Robert F
RF
Mullins
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Department of Biomedical Engineering.
Todd E
TE
Scheetz
The Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences.
Edwin M
EM
Stone
The Stephen A. Wynn Institute for Vision Research, Department of Biology, diane-slusarski@uiowa.edu.
Diane C
DC
Slusarski
D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins; D002478:Cells, Cultured; D059472:Exome; D015870:Gene Expression; D006801:Humans; D008297:Male; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics*; D000070778:Perilipin-1; D010750:Phosphoproteins; D012326:RNA Splicing; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult; D015027:Zebrafish
D002352:Carrier Proteins; D009711:Nucleotides; D000070778:Perilipin-1; D010750:Phosphoproteins; D009713:Nucleotidyltransferases; C000610948:TRNT1 protein, human