BACKGROUND & AIMS: Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now. METHODS: A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies. RESULTS: One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2). CONCLUSIONS: c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome. IMPACT AND IMPLICATIONS: The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.
- MeSH
- 5' nepřekládaná oblast genetika MeSH
- cholestáza * genetika MeSH
- HEK293 buňky MeSH
- intracelulární signální peptidy a proteiny * genetika MeSH
- lidé MeSH
- lymfedém * diagnóza genetika metabolismus MeSH
- myosiny genetika metabolismus MeSH
- novorozenec MeSH
- transportní proteiny genetika MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- akutní nemoc MeSH
- benzopyrany klasifikace terapeutické užití MeSH
- chronická nemoc MeSH
- lidé MeSH
- lymfatické nemoci * diagnóza patofyziologie terapie MeSH
- lymfatický systém anatomie a histologie růst a vývoj MeSH
- lymfedém genetika komplikace patofyziologie terapie MeSH
- nádory lymfatických cév klasifikace patofyziologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- echokardiografie metody využití MeSH
- hypertenze genetika komplikace MeSH
- kardiovaskulární abnormality diagnóza komplikace prevence a kontrola MeSH
- kardiovaskulární komplikace v těhotenství * diagnóza etiologie prevence a kontrola MeSH
- lidé MeSH
- lymfedém diagnóza genetika komplikace MeSH
- magnetická rezonanční tomografie metody využití MeSH
- mateřská mortalita MeSH
- preeklampsie diagnóza prevence a kontrola MeSH
- rizikové faktory MeSH
- ruptura aorty * genetika komplikace prevence a kontrola MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Turnerův syndrom * diagnóza etiologie komplikace MeSH
- vrozené srdeční vady diagnóza komplikace prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- MeSH
- genetické testování MeSH
- lidé MeSH
- lymfedém diagnóza genetika prevence a kontrola MeSH
- lymfografie MeSH
- preventivní lékařství MeSH
- výzkumný projekt MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
