TY - JOUR
T1 - Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome
AU - Otsuji, Shiomi
AU - Nishio, Yosuke
AU - Tsujita, Maki
AU - Rio, Marlene
AU - Huber, Céline
AU - Antón-Plágaro, Carlos
AU - Mizuno, Seiji
AU - Kawano, Yoshihiko
AU - Miyatake, Satoko
AU - Simon, Marleen
AU - van Binsbergen, Ellen
AU - van Jaarsveld, Richard H
AU - Matsumoto, Naomichi
AU - Cormier-Daire, Valerie
AU - J Cullen, Peter
AU - Saitoh, Shinji
AU - Kato, Kohji
N1 - Funding Information:
This study was partially supported by JSPS KAKENHI Grant Number JP20K21583 (SS), JP20H05700 (SS), JP19K23823 (KK), JP20K16897 (KK), JP20K07907 (SMiy), Japan Intractable Diseases (Nanbyo) Research Foundation (KK), Programme for an Integrated Database of Clinical and Genomic Information from the Japanese Agency for Medical Research and Development, AMED (SS). Work in the Matsumoto Laboratory is supported by AMED grants under the numbers JP21ek0109486, JP21ek0109549 and JP21ek0109493 (NM). Work in the Cullen Laboratory is supported by the Wellcome Trust (220260/Z/20/Z), the Medical Research Council (MR/L007363/1 and MR/P018807/1), the Lister Institute of Preventive Medicine and a Royal Society Noreen Murray Research Professorship to P.J.C (RSRP/R1/211004).
Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - PURPOSE: The Retriever subunit
VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after
WASHC5 and
CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS.
METHODS: We report three new patients with biallelic
VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology.
RESULTS: In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients with
CCDC22 and
WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake.
CONCLUSION: VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development.
AB - PURPOSE: The Retriever subunit
VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after
WASHC5 and
CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS.
METHODS: We report three new patients with biallelic
VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology.
RESULTS: In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients with
CCDC22 and
WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake.
CONCLUSION: VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development.
KW - Medical
KW - genetics
KW - medical
UR - https://www.scopus.com/pages/publications/85142512518
U2 - 10.1136/jmg-2022-108602
DO - 10.1136/jmg-2022-108602
M3 - Article
C2 - 36113987
SN - 0022-2593
VL - 60
SP - 359
EP - 367
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 4
M1 - 108602
ER -