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

Abstract

Marinesco-Sjögren syndrome (MSS) is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms that 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 MSS and the INPP5K-phenotype. We applied unbiased proteomic profiling on cells derived from MSS- and INPP5K-patients and identified alterations in D-3-phosphoglycerate dehydrogenase as a common molecular feature. D-3-phosphoglycerate dehydrogenase modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with MSS and INPP5K-disease. As, L-serine administration represents a promising therapeutic strategy for D-3-phosphoglycerate dehydrogenase 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.

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

“…The MTT assay is a colorimetric assay for assessing cell metabolic activity, reflecting the number of viable cells present and was applied as described before [ 52 ] on control (n = 3; grouped) and PORCN -patient derived fibroblasts. For each cell line eight technical replicates were analyzed under basal conditions and after Tunicamycin-treatment (see above).…”

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

“…Loss of INPP5K in humans affects the muscle, brain, and eyes and knockdown of inpp5ka in zebrafish larvae resulted in morphological abnormalities in the eyes and skeletal muscle (Hathazi et al, 2021; Osborn et al, 2017; Wiessner et al, 2017). We dissected the heads, eyes, and tails of developing larvae for tissue-specific expression analysis ( Fig.…”

“…In humans, much of the pathology resulting from mutations within INPP5K have been attributed to the dysregulation of phosphoinositide homeostasis (Hathazi et al, 2021; McGrath et al, 2020; Osborn et al, 2017; Wiessner et al, 2017). Most known mutations in INPP5K are missense variants occurring in the catalytic phosphatase domain reducing or ablating conversion of PtdIns(4,5)P 2 to PtdIns(4)P (Osborn et al, 2017; Wiessner et al, 2017).…”

“…Multiple zebrafish ( Danio rerio ) models of INPP5K loss of function have been generated using morpholino oligonucleotides (MOs) targeting both paralogs, inpp5ka and inpp5kb (Hathazi et al, 2021; Osborn et al, 2017; Wiessner et al, 2017). However, when the genes were targeted independently, knockdown of inpp5ka was sufficient to yield phenotypes typical of neurological and muscular disorders, such as microphthalmia, microcephaly, shortened body, reduced touch-evoked motility and myopathy.…”

“…Also referred to as skeletal muscle and kidney-enriched inositol phosphatase ( SKIP ), INPP5K is highly expressed in the brain, eyes, and muscles during development and adulthood (Gurung et al, 2003; Ijuin et al, 2000). In humans, homozygous or compound heterozygous mutations in INPP5K have been causally linked to a form of congenital muscular dystrophy with cataracts and intellectual disability (MIM: 617404) also associated with short stature, and microcephaly with considerable variability in the age of onset and early presentations (D’Amico et al, 2020; Hathazi et al, 2021; Osborn et al, 2017; Wiessner et al, 2017; Yousaf et al, 2017). Similarities have been noted with Marinesco-Sjögren syndrome (MIM: 248800), a form of myopathy also associated with congenital cataracts, short stature, and cerebellar ataxia (Krieger et al, 2013; Senderek et al, 2005).…”