Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A

Runar Almaas; Monica Atneosen-Åsegg; Mari Eknes Ytre-Arne; Maria Melheim; Hanne Sørmo Sorte; Dana Cízková; Henrik Mikael Reims; Aleš Bezrouk; Sean Philip Harrison; Janne Strand; Johanne Uthus Hermansen; Sofie Strøm Andersen; Kristin Louise Eiklid; Jaroslav Mokrý; Gareth John Sullivan; Asbjørg Stray-Pedersen

doi:10.1016/j.jhep.2023.05.037

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A

Runar Almaas^*, Monica Atneosen-Åsegg, Mari Eknes Ytre-Arne, Maria Melheim, Hanne Sørmo Sorte, Dana Cízková, Henrik Mikael Reims, Aleš Bezrouk, Sean Philip Harrison, Janne Strand, Johanne Uthus Hermansen, Sofie Strøm Andersen, Kristin Louise Eiklid, Jaroslav Mokrý, Gareth John Sullivan, Asbjørg Stray-Pedersen

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	945-954
Number of pages	10
Journal	Journal of Hepatology
Volume	79
Issue number	4
Early online date	14 Sept 2023
DOIs	https://doi.org/10.1016/j.jhep.2023.05.037
Publication status	Published - 1 Oct 2023

Keywords

Genetic
Cholestatis
Lymphedema
Myosin
UNC45A
Non-coding
Untranslated region
Bile acids
Non-coding variant

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jhep.2023.05.037Licence: CC BY

Almaas_2023_JoH_Aagenaes-syndrome-caused-variant-UNC45A_CC
© 2023 The Authors. This is an open access article distributed under the terms of the Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 4.24 MBLicence: CC BY

Cite this

Almaas, R., Atneosen-Åsegg, M., Ytre-Arne, M. E., Melheim, M., Sorte, H. S., Cízková, D., Reims, H. M., Bezrouk, A., Harrison, S. P., Strand, J., Hermansen, J. U., Andersen, S. S., Eiklid, K. L., Mokrý, J., Sullivan, G. J., & Stray-Pedersen, A. (2023). Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A. Journal of Hepatology, 79(4), 945-954. https://doi.org/10.1016/j.jhep.2023.05.037

@article{ef5f42aab9d7406aa970f66dc30ef541,

title = "Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A",

abstract = "Background & AimsLymphedema 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.MethodsA 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.ResultsOne specific variant (c.-98G>T) in the 5{\textquoteright}-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{\textquoteright}-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).Conclusionsc.-98G>T in the 5{\textquoteright}-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.",

keywords = "Genetic, Cholestatis, Lymphedema, Myosin, UNC45A, Non-coding, Untranslated region, Bile acids, Non-coding variant",

author = "Runar Almaas and Monica Atneosen-{\AA}segg and Ytre-Arne, {Mari Eknes} and Maria Melheim and Sorte, {Hanne S{\o}rmo} and Dana C{\'i}zkov{\'a} and Reims, {Henrik Mikael} and Ale{\v s} Bezrouk and Harrison, {Sean Philip} and Janne Strand and Hermansen, {Johanne Uthus} and Andersen, {Sofie Str{\o}m} and Eiklid, {Kristin Louise} and Jaroslav Mokr{\'y} and Sullivan, {Gareth John} and Asbj{\o}rg Stray-Pedersen",

year = "2023",

month = oct,

day = "1",

doi = "10.1016/j.jhep.2023.05.037",

language = "English",

volume = "79",

pages = "945--954",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "W B SAUNDERS CO",

number = "4",

}

Almaas, R, Atneosen-Åsegg, M, Ytre-Arne, ME, Melheim, M, Sorte, HS, Cízková, D, Reims, HM, Bezrouk, A, Harrison, SP, Strand, J, Hermansen, JU, Andersen, SS, Eiklid, KL, Mokrý, J, Sullivan, GJ & Stray-Pedersen, A 2023, 'Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A', Journal of Hepatology, vol. 79, no. 4, pp. 945-954. https://doi.org/10.1016/j.jhep.2023.05.037

TY - JOUR

T1 - Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A

AU - Almaas, Runar

AU - Atneosen-Åsegg, Monica

AU - Ytre-Arne, Mari Eknes

AU - Melheim, Maria

AU - Sorte, Hanne Sørmo

AU - Cízková, Dana

AU - Reims, Henrik Mikael

AU - Bezrouk, Aleš

AU - Harrison, Sean Philip

AU - Strand, Janne

AU - Hermansen, Johanne Uthus

AU - Andersen, Sofie Strøm

AU - Eiklid, Kristin Louise

AU - Mokrý, Jaroslav

AU - Sullivan, Gareth John

AU - Stray-Pedersen, Asbjørg

PY - 2023/10/1

Y1 - 2023/10/1

N2 - Background & AimsLymphedema 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.MethodsA 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.ResultsOne 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).Conclusionsc.-98G>T in the 5’-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.

AB - Background & AimsLymphedema 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.MethodsA 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.ResultsOne 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).Conclusionsc.-98G>T in the 5’-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.

KW - Genetic

KW - Cholestatis

KW - Lymphedema

KW - Myosin

KW - UNC45A

KW - Non-coding

KW - Untranslated region

KW - Bile acids

KW - Non-coding variant

U2 - 10.1016/j.jhep.2023.05.037

DO - 10.1016/j.jhep.2023.05.037

M3 - Article

C2 - 37328071

SN - 0168-8278

VL - 79

SP - 945

EP - 954

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 4

ER -

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this