BSPED2016 Oral Communications Oral Communications 5- Endocrine (8 abstracts)
Mutations in SGPL1, encoding sphingosine-1-phosphate lyase, cause a novel form of primary adrenal insufficiency with steroid resistant nephrotic syndrome
Rathi Prasad 1 , Avinaash Maharaj 1 , Eirini Meimaridou 1 , Paul van Veldhoven 2 , Federica Buonocore 3 , Eliana Barbagelata 4 , Ignacio Bergadá 4 , Hamilton Cassinelli 4 , Urmi Das 5 , Ruth Krone 6 , Moin Saleem 7 , Bulent Hacihamdioglu 8 , Erkan Sari 8 , Helen Storr 1 , John Achermann 3 , Leonardo Guasti 1 , Debora Braslavsky 4 , Tulay Guran 8 , Nanik Ram 9 & Lou Metherell 1
1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK; 2KULeuven, LIPIT, Leuven, Belgium; 3UCL Institute of Child Health, London, UK; 4Centro de Investigaciones, CONICET – FEI – División de Endocrinología Endocrinológicas “Dr. César Bergadá” (CEDIE), Hospital de Niños R. Gutierrez, Buenos Aires, Argentina; 5Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK; 6Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK; 7Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK; 8Department of Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey; 9Section for Endocrinology, Aga Khan University, Karachi, Pakistan.
Background: Primary adrenal insufficiency (PAI) is most commonly congenital in children. PAI is genetically heterogeneous with some gene defects causing syndromic disease. A third of patients have no genetic diagnosis meaning their prognosis is uncertain. We recently investigated families with a novel combination of PAI and steroid resistant nephrotic syndrome.
Objective and hypotheses: To discover the genetic defect underlying this syndrome.
Method: Whole exome sequencing (WES) was performed in two families with Sanger sequencing of SGPL1 to confirm segregation and screen further families.
Results: By WES and Sanger sequencing three different mutations in SGPL1 were identified in four families. All mutations were homozygous in affected individuals and heterozygous in their asymptomatic parents. Kindred 1, three patients had a novel missense mutation [c.665G>A; p.R222Q], the index case presented with PAI (8 m), developed focal segmental glomerulosclerosis (FSGS) at 2.5 y and received a kidney transplant aged 5 y. A younger sibling with similar clinical history (not sequenced) died (4 y) whilst an older sibling (8 y) and a cousin (3 y) have only PAI. Kindred 2, a child presenting with PAI had the p.R222Q mutation and at age 3.7 y has no renal phenotype. Kindred 3, a female baby presenting with PAI (6 m) had a novel in-frame deletion, [c.1633_1635delTTC; p.F545del] and developed FSGS (5 y) on follow-up, additional features included ichthyosis and neurological symptoms. Kindred 4, two affected siblings manifesting PAI, ichthyosis and nephrotic syndrome (<1 yr) had a canonical splice site change, [c.261+1G>A; p.?], the male sibling additionally presented with micropenis, unilateral cryptorchidism and neurological symptoms.
Conclusion: We have identified a novel, potentially progressive, disorder incorporating PAI and nephrotic syndrome amongst other features. Sphingosine-1-phosphate lyase (SGPL1) executes the final decisive step of the sphingolipid pathway, initiating irreversible cleavage of the lipid signalling molecule sphingosine-1-phosphate (S1P). This novel syndrome highlights the importance of the sphingolipid metabolic pathway in adrenal function. A genetic diagnosis for patients with this form of PAI is important for correct treatment, genetic counselling and screening for co-morbidities.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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