New missense variants in RELT causing hypomineralised amelogenesis imperfecta

Georgios Nikolopoulos,Mohammed E El‐Asrag,Anesha Patel,Chris F Inglehearn,Gina Murillo,Mary J O'Connell,Claire E.L Smith,Catriona J Brown,Alan J Mighell,Steven J Brookes

doi:10.1111/cge.13721

Abstract

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non‐syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix. Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT‐variant associated AI.

Highlights

Amelogenesis is the process by which dental enamel is formed during tooth development
Our findings extend the observed mutation spectrum, reveal a founder mutation common to three UK Pakistani families and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but suggest that RELT variants are not always associated with a broader, syndromic phenotype
The sequence of the human RELT protein was retrieved from Uniprot and a homology model was produced in silico, by selecting the structure with the lowest energy conformation and performing Molecular Dynamics simulations to examine the effects of the variants on the structure

Summary

| INTRODUCTION

Amelogenesis is the process by which dental enamel is formed during tooth development. There is a transition phase when the immature enamel reaches its final thickness, ECM secretion stops, and ECM proteins begin to be degraded in a controlled way. Discoloured, weak enamel can quickly break down causing pain, infection and early tooth loss with subsequent malocclusion. This in turn leads to high levels of distress, social avoidance, discomfort, isolation and emotional problems.[5]. Kim and co-workers reported one missense and two nonsense variants in the gene encoding Receptor Expressed in Lymphoid Tissues (RELT, OMIM: 611211), causing hypoplastic AI.[6] Affected individuals were of short stature and their medical history suggested increased susceptibility to childhood infection, potentially implying a syndromic form of AI.[6]. Our findings extend the observed mutation spectrum, reveal a founder mutation common to three UK Pakistani families and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but suggest that RELT variants are not always associated with a broader, syndromic phenotype

| MATERIALS AND METHODS

| RESULTS

| DISCUSSION