A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation

Bamborschke, Daniel; Pergande, Matthias; Becker, Kerstin; Koerber, Friederike; Dötsch, Jörg; Vierzig, Anne; Weber, Lutz T.; Çırak, Sebahattin

doi:10.1016/j.braindev.2018.02.008

Cited by 43 publications

(44 citation statements)

References 9 publications

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“…Similarly, the majority of affected individuals have adrenal disease (see Tables 2, 3). SGPL1 has a potential role to play in other endocrine tissues with emerging reports of wider endocrinopathy (thyroid and testicular), as seen in our patient (1,2,(5)(6)(7)(8)(9)). This appears to be unique to SPLIS in comparison to other sphingolipidoses.…”

Section: Discussionsupporting

confidence: 55%

“…Interestingly, mutations inherited in compound heterozygosity have been associated with isolated peripheral neuropathy akin to Charcot-Marie Tooth; the adult siblings described do not have additional disease (4). Lymphopenia is seen in some patients and is associated variably with an increased frequency of infections (1,2,5,9). SPLIS therefore encompasses a clinically heterogenous phenotype, with the most severe cases presenting with fetal hydrops, whilst others are affected with single organ disease alone.…”

Section: Discussionmentioning

confidence: 99%

“…The disease is associated with loss of function mutations in SGPL1, encoding sphingosine-1-phosphate lyase that irreversibly binds sphingosine 1-phosphate (S1P) and commits it to the final degradative step in sphingolipid metabolism (1)(2)(3). Phenotypic expression of the condition is variable, from severe multi-systemic forms, associated with fetal hydrops and early mortality, to isolated single organ disease (1,2,(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy

et al. 2020

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Background: Loss of function mutations in SGPL1 are associated with Sphingosine-1-phosphate lyase insufficiency syndrome, comprising steroid resistant nephrotic syndrome, and primary adrenal insufficiency (PAI) in the majority of cases. SGPL1 encodes sphingosine-1-phosphate lyase (SGPL1) which is a major modulator of sphingolipid signaling. Case Presentation: A Pakistani male infant presented at 5 months of age with failure to thrive, nephrotic syndrome, primary adrenal insufficiency, hypothyroidism, and hypogonadism. Other systemic manifestations included persistent lymphopenia, ichthyosis, and motor developmental delay. Aged 9 months, he progressed rapidly into end stage oligo-anuric renal failure and subsequently died. Sanger sequencing of the entire coding region of SGPL1 revealed the novel association of a rare homozygous mutation (chr10:72619152, c.511A>G, p.N171D; MAF−1.701e-05) with the condition. Protein expression of the p.N171D mutant was markedly reduced compared to SGPL1 wild type when overexpressed in an SGPL1 knockout cell line, and associated with a severe clinical phenotype. Conclusions: The case further highlights the emerging phenotype of patients with loss-of-function SGPL1 mutations. Whilst nephrotic syndrome is a recognized feature of other disorders of sphingolipid metabolism, sphingosine-1-phosphate lyase insufficiency syndrome is unique amongst the sphingolipidoses in presenting with multiple endocrinopathies. Given the multi-systemic and progressive nature of this form of PAI/ nephrotic syndrome, a genetic diagnosis is crucial for optimal management and appropriate screening for comorbidities in these patients.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy

et al. 2020

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“…Increased autophagy due to alterations in S1P levels was proposed as the underlying pathogenetic mechanism. 40 Preliminary lipidomics analysis of cellular sphingolipids in cultured fibroblast homogenates did not show significant abnormalities in SMPD4-deficient cells, compared to control subjects (G.M.S.M. and M.F., unpublished data).…”

Section: Er Stress and Autophagymentioning

confidence: 86%

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Magini

Smits

Vandervore

et al. 2019

The American Journal of Human Genetics

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Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

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“…15 In brief, genomic deoxyribonucleic acid (DNA) isolated from ethylenediaminetetraacetic acid (EDTA)-blood of the index patient was subjected to whole exome sequencing on an Illumina Hiseq 4000, using the SureSelect Human All Exon V6 enrichment kit and a paired-end 75bp sequencing protocol. Data analysis was performed with the VARBANK (v2.25) exome pipeline of the Cologne Center for Genomics, 16 including alignment against the human reference genome and variant calling. Sequencing data were filtered for rare (minor allele frequency < 0.1%), heterozygous variants in accordance with either autosomal recessive or the expected autosomal dominant inheritance pattern.…”

Section: Genetic Work-upmentioning

confidence: 99%

Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

et al. 2018

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Mutations in are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in (NM_021007, c.4949T> C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of -associated neurologic disorders, emphasizing that mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.

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A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation

Cited by 43 publications

References 9 publications

A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy

A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

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