ESPN 50th Annual Meeting

ESPN 2017


 
Mutations in LAMB2 are associated with FSGS and Septo-Optic Dysplasia
MONA TAHOUN 1 SCOTT HASSON 1 EMMA ASHTON 2 MEHUL DATTANI 1 AOIFE WATERS

1- UCL GREAT ORMOND STREET INSTITUTE OF CHILD HEALTH
2- GREAT ORMOND STREET HOSPITAL NHS FOUNDATION TRUST
 
Introduction:

Mutations in LAMB2, the gene encoding laminin-β2, a multidomain protein are associated with Pierson Syndrome, an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities including microcoria and neurodevelopmental delay. Very few patients survive to adolescence, with only 3 reported to date. We present an 11 year old male born to a non-consanguineous pedigree, who presented at 5 years of age with steroid resistant nephrotic syndrome and focal segmental glomerulosclerosis together with poor vision, growth hormone deficiency and seizures. MRI of his brain showed a global lack of white matter, a small anterior pituitary and bilateral hypoplastic optic nerves, features which are reminiscent of septo-optic dysplasia (SOD). His current estimated eGFR is 59mls/min/1.73m2 with urine albumin/creatinine ratio measuring 834mg/mmol with his medications consisting of angiotensin receptor blockade. SOD is characterized by the presence of two or more of the following: hypopituitarism with isolated or combined hormone deficiencies, optic nerve hypoplasia and/or midline brain defects including absence of the corpus callosum and septum pellucidum. The pathogenesis of SOD is multifactorial arising from either environmental causes, viral infections and alcohols. A hereditary aetiology has also been described with recessive and dominant cases reported and several genes implicated including HESX1 which plays a key role in pituitary morphogenesis. We describe a known SRNS disease gene implicated in SOD phenotype presenting with childhood onset FSGS.

Material and methods:

Genetic analysis was undertaken using whole exome sequencing with validation by Sanger sequencing. Dual immunofluorescent microscopy was employed to validate loss of function and expression in patient biopsies relative to controls.

Results:

Using whole exome sequencing, we identified compound heterozygous missense mutations in LAMB2 [c.737G>A p.Arg246Gln, c.3982G>A p.Gly1328Ser]. Dual immunofluorescent histochemistry revealed reduced glomerular laminin-β2 expression compared to control biopsies [time zero renal transplant]. Interestingly, laminin β2 is expressed during murine anterior pituitary morphogenesis and analysis of murine Lamb2 mutant pituitary morphogenesis is currently underway.

Conclusions:

Our case raises the possibility that mutations in LAMB2 may be associated with SOD-related phenotypes. We propose that patients presenting with genetically undefined SOD should be screened for albuminuria.