8

UCL INSTITUTE OF CHILD HEALTH

MSc in Paediatrics and Child Health

and

MSc in Cell & Gene Therapy

CHLDGX05

Molecular & Genetic Basis of Paediatrics

COVER SHEET

Essay: due 12.00 midday Monday 5th January 2015

CANDIDATE NUMBER*	FCQK6
Word Count 1500 MAX (excluding the title, references, 4 key highlights/learning points and the 2 key references)	1591

Critical review of a journal article: mutation-dependent recessive inheritance of nphs2- associated steroid-resistant nephrotic syndrome Learning Points

• Steroid-resistant form of nephrotic syndrome is due to over twenty mutations, most of which encode for the podocyte proteins. The podocytes usually accumulate in oligomeric or dimeric forms in the podocyte slit diaphragm within the glomerular filtration barrier. Therefore, mutations that affect the protein affects the pathogenicity of the disease.

• Children can inherit the genetic mutations from unaffected obligate mutation carriers for p.Arg229Gln. This is due to its inheritance in a mutation-dependent recessive fashion

• The pathogenicity of the disease depends on allele frequency of p.Arg229Gl. For example, in the late onset steroid-resistant nephrotic syndrome there is a high frequency of the allele p.Arg229Gl leading to its specific pathogenicity.

• The podocin, a protein encoded by p.Arg229Gl gene, has two forms; the dimmer and oligomer. The oligomer form of the protein is caused by several mutations and is responsible for the pathogenicity of the disease.

Abstract

This paper provides a critique of the article ‘Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome’ by Tory et al. (2014). The article investigates the NPHS2 specific mutations that affect the recessive inheritance of steroid-resistant nephrotic syndrome. The study finds that the NPHS2 allele encoding p.Arg229Gln must be associated with specific mutations in order to cause the pathogenicity, therefore concluding that nephrotic syndrome is inherited in mutation-dependent recessive fashion.

Introduction

Tory et al., (2014) present type 2 nephrotic syndrome as an autosomal recessive disorder caused by NPHS2 allele encoding the p.Arg229Gln gene. Current genetic knowledge indicates that autosomal-recessive disorders are only caused by the disease causing-variant without the influence of the other variant. However, the researchers argue that the allele only leads to disease when associated with specific 3′ NPHS2 mutations. The study provides medical and gentic background, showing that nephrotic syndrome is a clinical condition resulting from damage to the glomerular filtration barrier. The steroid-resistant form of the condition is associated with several genetic mutations. The study established that some parents who were not affected by the condition had children with the disorder. An analysis of their genetic make up revealed that there were specific mutations associated with the NPHS2 allele. The researchers conclude that other autosomal-recessive disorders can be inherited in a mutation-dependent fashion especially when the encoded protein has the ability to form oligomers (Tory et al. 2014).