PreprintCC BYbioRxiv7 Oct 2026

CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis

P. K. Sheokand
A. M. James
C. Posern
A. Singh Sahrawat
J. Breithofer
J. Ganellin
M. K. Proulx
S. K. Leese
K. Turner
D. Lacabanne
D. Bulfon
B. Jenkins

18 more authors

J. van der Kleij
H. E. Johnston
S. O. Lord
M. K. Basran
C. S. Yu
C. D. Booth
J. M. Weimer
A. Koulman
M. Jäättelä
E. R. S. Kunji
D. N. Palmer
N. L. Mitchell
J. Prudent
R. Zimmermann
K. Gruber
A. Schulz
M. P. Murphy
K. Petkevicius¹

¹MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK

Abstract

Lysosomal catabolism depends on bis(monoacylglycero)phosphate (BMP), a phospholipid with atypical S,S stereochemistry of unknown biosynthetic origin. CLN8 and CLN5 catalyze sequential acylation steps in BMP synthesis, and their loss of function causes Batten disease, a group of inherited neurodegenerative lysosomal storage disorders. Here we identify CLN6, a biochemically uncharacterized endoplasmic reticulum protein whose loss also causes Batten disease, as the calcium-dependent glycerophosphoglycerol epimerase that establishes BMP stereochemistry upstream of CLN8. CLN6 deficiency depletes BMP in cells, mice, and patient lysosomes, and reduces lysosomal hydrolase levels. BMP-precursor supplementation bypasses CLN6, restores BMP and increases hydrolase abundance in CLN6-deficient cells and mice. These findings place three Batten disease proteins in a single biosynthetic pathway and reveal BMP deficiency as a reversible cause of disrupted lysosomal hydrolase homeostasis.

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BibTeX

@misc{sheokand2026cln6,
  title = {{CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis}},
  author = {P. K. Sheokand and A. M. James and C. Posern and A. Singh Sahrawat and J. Breithofer and J. Ganellin and M. K. Proulx and S. K. Leese and K. Turner and D. Lacabanne and D. Bulfon and B. Jenkins and J. van der Kleij and H. E. Johnston and S. O. Lord and M. K. Basran and C. S. Yu and C. D. Booth and J. M. Weimer and A. Koulman and M. Jäättelä and E. R. S. Kunji and D. N. Palmer and N. L. Mitchell and J. Prudent and R. Zimmermann and K. Gruber and A. Schulz and M. P. Murphy and K. Petkevicius},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.07.757350},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757350v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis
AU  - P. K. Sheokand
AU  - A. M. James
AU  - C. Posern
AU  - A. Singh Sahrawat
AU  - J. Breithofer
AU  - J. Ganellin
AU  - M. K. Proulx
AU  - S. K. Leese
AU  - K. Turner
AU  - D. Lacabanne
AU  - D. Bulfon
AU  - B. Jenkins
AU  - J. van der Kleij
AU  - H. E. Johnston
AU  - S. O. Lord
AU  - M. K. Basran
AU  - C. S. Yu
AU  - C. D. Booth
AU  - J. M. Weimer
AU  - A. Koulman
AU  - M. Jäättelä
AU  - E. R. S. Kunji
AU  - D. N. Palmer
AU  - N. L. Mitchell
AU  - J. Prudent
AU  - R. Zimmermann
AU  - K. Gruber
AU  - A. Schulz
AU  - M. P. Murphy
AU  - K. Petkevicius
PY  - 2026
DA  - 2026/10/07
PB  - bioRxiv
DO  - 10.64898/2026.10.07.757350
UR  - https://www.biorxiv.org/content/10.64898/2026.10.07.757350v1
AB  - Lysosomal catabolism depends on bis(monoacylglycero)phosphate (BMP), a phospholipid with atypical S,S stereochemistry of unknown biosynthetic origin. CLN8 and CLN5 catalyze sequential acylation steps in BMP synthesis, and their loss of function causes Batten disease, a group of inherited neurodegenerative lysosomal storage disorders. Here we identify CLN6, a biochemically uncharacterized endoplasmic reticulum protein whose loss also causes Batten disease, as the calcium-dependent glycerophosphoglycerol epimerase that establishes BMP stereochemistry upstream of CLN8. CLN6 deficiency depletes BMP in cells, mice, and patient lysosomes, and reduces lysosomal hydrolase levels. BMP-precursor supplementation bypasses CLN6, restores BMP and increases hydrolase abundance in CLN6-deficient cells and mice. These findings place three Batten disease proteins in a single biosynthetic pathway and reveal BMP deficiency as a reversible cause of disrupted lysosomal hydrolase homeostasis.
ER  -

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