The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.

Behzad Davarniya,H Hilger Ropers,Masoumeh Hosseini,Luciana Musante,Zohreh Fattahi,Hossein Najmabadi,Kimia Kahrizi,Fariba Maqsoud,Hao Hu,Thomas F Wienker,Reza Farajollahi,Dror Sharon

doi:10.1371/journal.pone.0129631

Abstract

Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1–3% of the world’s population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.

Highlights

Cognitive impairment or intellectual disability (ID) is estimated to affect up to 3% of the general population and can be caused by both environmental and genetic factors, such as chromosomal aberrations or autosomal recessive, dominant, X-linked or mitochondrial mutations
Studies of the molecular basis of intellectual disability have focused on X-linked ID in part, because the larger families which is needed for gene mapping in autosomal recessive intellectual disorder (ARID) are rare in Western countries
We present two of these families in which autozygosity mapping and next-generation sequencing (NGS) led to the identification of a homozygous 2 bp deletion in TRMT1 gene (OMIMÃ611669) and a homozygous missense change in GRM1 gene (OMIM#604473)

Summary

Introduction

Cognitive impairment or intellectual disability (ID) is estimated to affect up to 3% of the general population and can be caused by both environmental and genetic factors, such as chromosomal aberrations or autosomal recessive, dominant, X-linked or mitochondrial mutations. ID can be divided into two main groups: non-syndromic (NS) ID, where it might present with ID without additional features, and syndromic ID, in which additional clinical or dysmorphic features may be present [1, 2, 3]. Studies of the molecular basis of intellectual disability have focused on X-linked ID in part, because the larger families which is needed for gene mapping in ARID are rare in Western countries. In families from the Middle East, autosomal recessive disorders were found to be approximately three times more frequent among inbred vs non-inbred families [5]

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