TY - JOUR
T1 - Lymphedema as first clinical presentation of Cantu Syndrome
T2 - reversed phenotyping after identification of gain-of-function variant in ABCC9
AU - Gao, Jian
AU - McClenaghan, Conor
AU - Christiaans, Imke
AU - Alders, Marielle
AU - van Duinen, Kirsten
AU - van Haelst, Mieke M.
AU - van Haaften, Gijs
AU - Nichols, Colin G.
N1 - Funding Information:
These studies were supported by R35 grant HL140024 from the NIH (to CGN), R21 grant HD103347 (to Dorothy K. Grange and CGN), K99 grant HL150277 (to CMC) and the E-Rare Joint Transnational Cantú Treat program I-2101-B26 (to GvH).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2023/2
Y1 - 2023/2
N2 - Cantu Syndrome (CS), [OMIM #239850] is characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly. CS is caused by gain-of-function (GOF) variants in the KCNJ8 or ABCC9 genes that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. Many subjects with CS also present with the complication of lymphedema. A previously uncharacterized, heterozygous ABCC9 variant, p.(Leu1055_Glu1058delinsPro), termed indel1055, was identified in an individual diagnosed with idiopathic lymphedema. The variant was introduced into the equivalent position of rat SUR2A, and inside-out patches were used to characterize the KATP channels formed by Kir6.2 and WT or mutant SUR2A subunits coexpressed in Cosm6 cells. The indel1055 variant causes gain-of-function of the channel, with an increase of the IC50 for ATP inhibition compared to WT. Retrospective consideration of this individual reveals clear features of Cantu Syndrome. An additional heterozygous ABCC9 variant, p.(Ile419Thr), was identified in a second individual diagnosed with lymphedema. In this case, there were no additional features consistent with CS, and the properties of p.(Ile416Thr) (the corresponding mutation in rat SUR2A)--containing channels were not different from WT. This proof-of-principle study shows that idiopathic lymphedema may actually be a first presentation of otherwise unrecognized Cantu Syndrome, but molecular phenotyping of identified variants is necessary to confirm relevance.
AB - Cantu Syndrome (CS), [OMIM #239850] is characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly. CS is caused by gain-of-function (GOF) variants in the KCNJ8 or ABCC9 genes that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. Many subjects with CS also present with the complication of lymphedema. A previously uncharacterized, heterozygous ABCC9 variant, p.(Leu1055_Glu1058delinsPro), termed indel1055, was identified in an individual diagnosed with idiopathic lymphedema. The variant was introduced into the equivalent position of rat SUR2A, and inside-out patches were used to characterize the KATP channels formed by Kir6.2 and WT or mutant SUR2A subunits coexpressed in Cosm6 cells. The indel1055 variant causes gain-of-function of the channel, with an increase of the IC50 for ATP inhibition compared to WT. Retrospective consideration of this individual reveals clear features of Cantu Syndrome. An additional heterozygous ABCC9 variant, p.(Ile419Thr), was identified in a second individual diagnosed with lymphedema. In this case, there were no additional features consistent with CS, and the properties of p.(Ile416Thr) (the corresponding mutation in rat SUR2A)--containing channels were not different from WT. This proof-of-principle study shows that idiopathic lymphedema may actually be a first presentation of otherwise unrecognized Cantu Syndrome, but molecular phenotyping of identified variants is necessary to confirm relevance.
UR - http://www.scopus.com/inward/record.url?scp=85141405224&partnerID=8YFLogxK
U2 - 10.1038/s41431-022-01210-x
DO - 10.1038/s41431-022-01210-x
M3 - Article
C2 - 36336713
AN - SCOPUS:85141405224
SN - 1018-4813
VL - 31
SP - 188
EP - 194
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 2
ER -