Tália Magdolna Keszthelyi1, 2
Máté Varga 3
Dorottya Ralbovszki 3
Christine Bole 4
Kálmán Tory 1,2
1: First Department of Pediatrics, Semmelweis University, 1083, Budapest, Hungary
2: MTA-SE Lendület Nephrogenetic Laboratory, Hungarian Academy of Sciences
3: ELTE, Department of Genetics
4: Inserm UMR1163, Imagine Institute, France
Association of polycystic kidney, cerebral atrophy and truncus arteriosus had not been reported in the medical literature.
We aimed to identify the causal gene and to explore the functions and the characteristics of the encoded protein in a 5-year-old boy with the above phenotype.
Whole exome sequencing was performed to identify the causal mutations. RNA expression was studied in leukocytes to investigate the nonsense-mediated decay. The localization of the mutant and the wild type protein was studied by immunofluorescence under confocal microscopy in transiently transfected IMCD3 cells after the induction of ciliogenesis. Mutant zebrafish lines were generated by the CRISPR/Cas9 system.
We identified compound heterozygous truncating mutations in the TMEM260 gene: c.592_593delTT, p.Leu198Valfs44* and c.1854C>A (p.Tyr618*). We verified their trans-association by Sanger sequencing of the parental samples. We found both mutated alleles to be equally expressed in the parental samples, indicating that none of them leads to nonsense-mediated decay. The p.Tyr618* mutation affects only the long isoform, allowing the short isoform to be properly translated. We successfully generated several tmem260 loss-of-function mutations and found the adult zebra danio mutants to develop a distorted shape. In contrast to the proteins implicated in ciliary kidney disorders, the TMEM260 protein was not detectable in the primary cilium but only in the plasma membrane.
Mutations of TMEM260 cause autosomal recessive polycystic kidney, cerebral atrophy and truncus arteriosus. TMEM260 is the first protein mutated in a cystic kidney disease which is not localized in the primary cilium. Our results are strongly supported by a very recent publication indicating the role of TMEM260 in this syndrome. The preserved translation of the short isoform in all three affected families strongly suggest that the dysfunction of the short isoform is intrauterine lethal.
Doctoral School: Clinical Medicine
Program: Prevention of Chronic Diseases in Childhood
Supervisor: Kálmán Tory