Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.
Rathi
R
Prasad
Irene
I
Hadjidemetriou
Avinaash
A
Maharaj
Eirini
E
Meimaridou
Federica
F
Buonocore
Moin
M
Saleem
Jenny
J
Hurcombe
Agnieszka
A
Bierzynska
Eliana
E
Barbagelata
Ignacio
I
Bergadá
Hamilton
H
Cassinelli
Urmi
U
Das
Ruth
R
Krone
Bulent
B
Hacihamdioglu
Erkan
E
Sari
Ediz
E
Yesilkaya
Helen L
HL
Storr
Maria
M
Clemente
Monica
M
Fernandez-Cancio
Nuria
N
Camats
Nanik
N
Ram
John C
JC
Achermann
Paul P
PP
Van Veldhoven
Leonardo
L
Guasti
Debora
D
Braslavsky
Tulay
T
Guran
Louise A
LA
Metherell
D000311:Adrenal Glands / Q000201:enzymology / Q000473:pathology; D000309:Adrenal Insufficiency / Q000151:congenital* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000446:Aldehyde-Lyases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D054643:INDEL Mutation; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)