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.

Department of Histology and Embryology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Medical Biophysics Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Medical Genetics Oslo University Hospital Oslo Norway

Department of Pediatric Research Division of Paediatric and Adolescent Medicine Oslo University Hospital Pb 4950 Nydalen Oslo Norway

Department of Pediatric Research Division of Paediatric and Adolescent Medicine Oslo University Hospital Pb 4950 Nydalen Oslo Norway; European Reference Network Rare Liver

Department of Pediatric Research Division of Paediatric and Adolescent Medicine Oslo University Hospital Pb 4950 Nydalen Oslo Norway; Institute of Clinical Medicine University of Oslo Oslo Norway; Department of Paediatrics Division of Paediatric and Adolescent Medicine Oslo University Hospital Pb 4950 Nydalen Oslo Norway; European Reference Network Rare Liver

Department of Pediatric Research Division of Paediatric and Adolescent Medicine Oslo University Hospital Pb 4950 Nydalen Oslo Norway; Institute of Clinical Medicine University of Oslo Oslo Norway; European Reference Network Rare Liver

European Reference Network Rare Liver; Department of Pathology Oslo University Hospital Oslo Norway

European Reference Network Rare Liver; Norwegian National Unit for Newborn Screening Division of Paediatric and Adolescent Medicine Oslo University Hospital Oslo Norway

Institute of Clinical Medicine University of Oslo Oslo Norway

Norwegian National Unit for Newborn Screening Division of Paediatric and Adolescent Medicine Oslo University Hospital Oslo Norway

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