Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction

Maharaj, Avinaash; Williams, Jack; Bradshaw, Teisha Y.; Güran, Tülay; Braslavsky, Débora; Casas, Josefina; Chan, Li F.; Metherell, Louise A.; Prasad, Rathi

doi:10.1016/j.jsbmb.2020.105730

Cited by 21 publications

(13 citation statements)

References 48 publications

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“…The constellation of adrenal, gonadal and thyroid disease is described in one other non-autoimmune-inherited form of adrenal insufficiency secondary to mutations in nicotinamide nucleotide transhydrogenase ( NNT ), involved in energy transfer in the mitochondrial respiratory chain ( 44 ), although there have now also been reports of hypothyroidism adding to the phenotype of adrenal and gonadal insufficiency in MIRAGE syndrome secondary to gain of function mutations in SAMD9 ( 45 ). Endocrine dysfunction can also be a feature of primary mitochondrial disorders associated with disruption of mitochondrial ATP production required for hormone synthesis and secretion ( 46 ). Indeed, perturbation of mitochondrial dynamics is seen in SPLIS patient dermal fibroblasts with subsequent impact on steroidogenesis ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Endocrine dysfunction can also be a feature of primary mitochondrial disorders associated with disruption of mitochondrial ATP production required for hormone synthesis and secretion (46). Indeed, perturbation of mitochondrial dynamics is seen in SPLIS patient dermal fibroblasts with subsequent impact on steroidogenesis (47). Mitochondrial disruption may account for the There are limited reports of endocrinopathy in other sphingolipid diseases, which are in the main lysosomal storage disorders (48).…”

Section: Discussionmentioning

confidence: 99%

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A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

Maharaj

Kwong

Williams

et al. 2022

Endocrine Connections

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Sphingosine-1-phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is an autosomal recessive multi-system disorder, which mainly incorporates steroid-resistant nephrotic syndrome and primary adrenal insufficiency. Further variable endocrine manifestations are described. We aimed to comprehensively annotate the endocrinopathies associated with pathogenic SGPL1 variants and assess for genotype-phenotype correlations by retrospectively reviewing reports of endocrine disease within our patient cohort and all published cases in the wider literature up to January 2022. Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, a third of these individuals have additional mineralocorticoid deficiency. Whilst most individuals also have nephrotic syndrome, SGPL1 variants also account for isolated adrenal insufficiency at presentation. Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one third of affected boys, all with concomitant adrenal disease. Mild primary hypothyroidism affects approximately a third of patients. There is paucity of data on the impact of SGPL1 deficiency on growth, and pubertal development, limited by the early and high mortality rate (approximately 50%). There is no clear genotype-phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds. However, with regards to endocrine phenotype the most prevalent disease variant p.R222Q (affecting 22%) is most consistently associated with isolated glucocorticoid deficiency. We conclude that SPLIS is associated with significant multiple endocrine disorders. Whilst endocrinopathy in the syndrome generally presents in infancy, late onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

Maharaj

Kwong

Williams

et al. 2022

Endocrine Connections

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“…SGPL1 is heavily involved in steroidogenesis, but is also implicated in several other cellular processes including redox regulation [ 11 ]. SGPL1 catalyses the terminal irreversible step in the sphingolipid degradation pathway, thereby controlling the cellular concentrations of harmful sphingolipid intermediates (such as ceramide) [ 43 ]. Ceramide acts as a key second messenger for steroidogenesis, decreasing steroid hormone production.…”

Section: Genetic Profiling Of Mitochondrial Genesmentioning

confidence: 99%

“…Ceramide acts as a key second messenger for steroidogenesis, decreasing steroid hormone production. Increases in SGPL1 activity reduce cellular levels of ceramide, and consequently increases cortisol biosynthesis [ 43 ]. Pathological accumulation of sphingolipid intermediates disrupts the IMM, causing mitochondrial dysfunction [ 43 ].…”

Section: Genetic Profiling Of Mitochondrial Genesmentioning

confidence: 99%

“…Increases in SGPL1 activity reduce cellular levels of ceramide, and consequently increases cortisol biosynthesis [ 43 ]. Pathological accumulation of sphingolipid intermediates disrupts the IMM, causing mitochondrial dysfunction [ 43 ]. As established, the IMM is the location of many key mitochondrial redox systems including the UCP and NNT proteins.…”

Section: Genetic Profiling Of Mitochondrial Genesmentioning

confidence: 99%

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Adrenal Dysfunction in Mitochondrial Diseases

Corkery-Hayward

Metherell

2023

IJMS

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Cortisol is central to several homeostatic mechanisms including the stress and immune response. Adrenal insufficiency and impaired cortisol production leads to severe, potentially fatal disorders. Several fundamental stages of steroidogenesis occur within the mitochondria. These dynamic organelles not only contribute ATP for steroidogenesis, but also detoxify harmful by-products generated during cortisol synthesis (reactive oxygen species). Mutations in nuclear or mitochondrial DNA that impair mitochondrial function lead to debilitating multi-system diseases. Recently, genetic variants that impair mitochondrial function have been identified in people with isolated cortisol insufficiency. This review aimed to clarify the association between mitochondrial diseases and adrenal insufficiency to produce cortisol. Mitochondrial diseases are rare and mitochondrial diseases that feature adrenal insufficiency are even rarer. We identified only 14 cases of adrenal insufficiency in people with confirmed mitochondrial diseases globally. In line with previous reviews, adrenal dysfunction was most prevalent in mitochondrial deletion syndromes (particularly Pearson syndrome and Kearns–Sayre syndrome) and with point mutations that compromised oxidative phosphorylation. Although adrenal insufficiency has been reported with mitochondrial diseases, the incidence reflects that expected in the general population. Thus, it is unlikely that mitochondrial mutations alone are responsible for an insufficiency to produce cortisol. More research is needed into the pathogenesis of adrenal disease in these individuals.

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Development and function of the fetal adrenal

Pignatti

Toit

Flueck

2022

Rev Endocr Metab Disord

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The adrenal cortex undergoes multiple structural and functional rearrangements to satisfy the systemic needs for steroids during fetal life, postnatal development, and adulthood. A fully functional adrenal cortex relies on the proper subdivision in regions or ‘zones’ with distinct but interconnected functions, which evolve from the early embryonic stages to adulthood, and rely on a fine-tuned gene network. In particular, the steroidogenic activity of the fetal adrenal is instrumental in maintaining normal fetal development and growth. Here, we review and discuss the most recent advances in our understanding of embryonic and fetal adrenal development, including the known causes for adrenal dys-/agenesis, and the steroidogenic pathways that link the fetal adrenal with the hormone system of the mother through the fetal-placental unit. Finally, we discuss what we think are the major open questions in the field, including, among others, the impact of osteocalcin, thyroid hormone, and other hormone systems on adrenal development and function, and the reliability of rodents as models of adrenal pathophysiology.

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Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction

Cited by 21 publications

References 48 publications

A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

Adrenal Dysfunction in Mitochondrial Diseases

Development and function of the fetal adrenal

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