INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

Denisa Hathazi; Dan Cox; Adele D'Amico; Giorgio Tasca; Richard Charlton; Robert Yves Carlier; Jennifer Baumann; Laxmikanth Kollipara; René P. Zahedi; Ingo Feldmann; Jean Francois Deleuze; Annalaura Torella; Ronald Cohn; Emily Robinson; Francesco Ricci; Heinz Jungbluth; Fabiana Fattori; Anne Boland; Emily O'Connor; Rita Horvath; Rita Barresi; Hanns Lochmüller; Andoni Urtizberea; Marie Line Jacquemont; Isabelle Nelson; Laura Swan; Gisèle Bonne; Andreas Roos

doi:10.1093/brain/awab133

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

Denisa Hathazi, Dan Cox, Adele D'Amico, Giorgio Tasca, Richard Charlton, Robert Yves Carlier, Jennifer Baumann, Laxmikanth Kollipara, René P. Zahedi, Ingo Feldmann, Jean Francois Deleuze, Annalaura Torella, Ronald Cohn, Emily Robinson, Francesco Ricci, Heinz Jungbluth, Fabiana Fattori, Anne Boland, Emily O'Connor, Rita HorvathRita Barresi, Hanns Lochmüller, Andoni Urtizberea, Marie Line Jacquemont, Isabelle Nelson, Laura Swan, Gisèle Bonne, Andreas Roos

Randall Centre of Cell & Molecular Biophysics

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

9 Citations (Scopus)

Abstract

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Original language	English
Pages (from-to)	2427-2442
Number of pages	16
Journal	Brain
Volume	144
Issue number	8
DOIs	https://doi.org/10.1093/brain/awab133
Publication status	Published - 1 Aug 2021

Keywords

BiP
INPP5K
L-serine
PHGDH
SIL1

Access to Document

10.1093/brain/awab133

Cite this

Hathazi, D., Cox, D., D'Amico, A., Tasca, G., Charlton, R., Carlier, R. Y., Baumann, J., Kollipara, L., Zahedi, R. P., Feldmann, I., Deleuze, J. F., Torella, A., Cohn, R., Robinson, E., Ricci, F., Jungbluth, H., Fattori, F., Boland, A., O'Connor, E., ... Roos, A. (2021). INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain, 144(8), 2427-2442. https://doi.org/10.1093/brain/awab133

@article{21eeea65f41c46aaa3b6f936ae11c026,

title = "INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH",

abstract = "Marinesco-Sj{\"o}gren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sj{\"o}gren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sj{\"o}gren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sj{\"o}gren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.",

keywords = "BiP, INPP5K, L-serine, PHGDH, SIL1",

author = "Denisa Hathazi and Dan Cox and Adele D'Amico and Giorgio Tasca and Richard Charlton and Carlier, {Robert Yves} and Jennifer Baumann and Laxmikanth Kollipara and Zahedi, {Ren{\'e} P.} and Ingo Feldmann and Deleuze, {Jean Francois} and Annalaura Torella and Ronald Cohn and Emily Robinson and Francesco Ricci and Heinz Jungbluth and Fabiana Fattori and Anne Boland and Emily O'Connor and Rita Horvath and Rita Barresi and Hanns Lochm{\"u}ller and Andoni Urtizberea and Jacquemont, {Marie Line} and Isabelle Nelson and Laura Swan and Gis{\`e}le Bonne and Andreas Roos",

year = "2021",

month = aug,

day = "1",

doi = "10.1093/brain/awab133",

language = "English",

volume = "144",

pages = "2427--2442",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "8",

}

Hathazi, D, Cox, D, D'Amico, A, Tasca, G, Charlton, R, Carlier, RY, Baumann, J, Kollipara, L, Zahedi, RP, Feldmann, I, Deleuze, JF, Torella, A, Cohn, R, Robinson, E, Ricci, F, Jungbluth, H, Fattori, F, Boland, A, O'Connor, E, Horvath, R, Barresi, R, Lochmüller, H, Urtizberea, A, Jacquemont, ML, Nelson, I, Swan, L, Bonne, G & Roos, A 2021, 'INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH', Brain, vol. 144, no. 8, pp. 2427-2442. https://doi.org/10.1093/brain/awab133

TY - JOUR

T1 - INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

AU - Hathazi, Denisa

AU - Cox, Dan

AU - D'Amico, Adele

AU - Tasca, Giorgio

AU - Charlton, Richard

AU - Carlier, Robert Yves

AU - Baumann, Jennifer

AU - Kollipara, Laxmikanth

AU - Zahedi, René P.

AU - Feldmann, Ingo

AU - Deleuze, Jean Francois

AU - Torella, Annalaura

AU - Cohn, Ronald

AU - Robinson, Emily

AU - Ricci, Francesco

AU - Jungbluth, Heinz

AU - Fattori, Fabiana

AU - Boland, Anne

AU - O'Connor, Emily

AU - Horvath, Rita

AU - Barresi, Rita

AU - Lochmüller, Hanns

AU - Urtizberea, Andoni

AU - Jacquemont, Marie Line

AU - Nelson, Isabelle

AU - Swan, Laura

AU - Bonne, Gisèle

AU - Roos, Andreas

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

AB - Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

KW - BiP

KW - INPP5K

KW - L-serine

KW - PHGDH

KW - SIL1

UR - http://www.scopus.com/inward/record.url?scp=85115905290&partnerID=8YFLogxK

U2 - 10.1093/brain/awab133

DO - 10.1093/brain/awab133

M3 - Article

C2 - 33792664

AN - SCOPUS:85115905290

SN - 0006-8950

VL - 144

SP - 2427

EP - 2442

JO - Brain

JF - Brain

IS - 8

ER -

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this