PhD Scientific Days 2018

Poster presentations: Molecular medicine

Identification of a novel gene in a patient with polycystic kidney, cerebral atrophy and truncus arteriosus

Előadó neve

Keszthelyi, Tália Magdolna

Előadó munkahelye

First Department of Pediatrics, Semmelweis University, 1083, Budapest, Hungary

Előadó telefonszáma

+36205269772

Előadó e-mail címe

keszthelyi0527@gmail.com

Az előadás címe

Identification of a novel gene in a patient with polycystic kidney, cerebral atrophy and truncus arteriosus

Szerző(k) neve és munkahelye

Tália Magdolna Keszthelyi1, 2
Máté Varga 3
Dorottya Ralbovszki 3
Christine Bole 4
Corinne Antignac4
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

Bemutatás módja

Szóbeli

Szekció

Poster presentations: Molecular medicine

Language of the presentation

Hungarian

Témacsoport

molecular sciences

Összefoglaló szövege

Introduction
Association of polycystic kidney, cerebral atrophy and truncus arteriosus had not been reported in the medical literature.

Aims
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.

Methods
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.

Results
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.

Conclusion
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.

Data of the presenter

Doctoral School: Clinical Medicine
Program: Prevention of Chronic Diseases in Childhood
Supervisor: Kálmán Tory
E-mail: keszthelyi0527@gmail.com

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

2797

Presentation file URL

//docs.kmcongress.com/phd2018/eposter_4469.jpeg

Authors (legacy)

Tália Magdolna Keszthelyi1, 2
Máté Varga 3
Dorottya Ralbovszki 3
Christine Bole 4
Corinne Antignac4
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