title: The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.
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.
authors: Genetics Research Center (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors: Behzad
authors: B
authors: Davarniya
authors: Department of Human Molecular Genetics, Max-Plank Institute for Molecular Genetics, Berlin, Germany.
authors: Hao
authors: H
authors: Hu
authors: Genetics Research Center (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors: Kimia
authors: K
authors: Kahrizi
authors: Department of Human Molecular Genetics, Max-Plank Institute for Molecular Genetics, Berlin, Germany.
authors: Luciana
authors: L
authors: Musante
authors: Genetics Research Center (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors: Zohreh
authors: Z
authors: Fattahi
authors: Genetics Research Center (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors: Masoumeh
authors: M
authors: Hosseini
authors: Welfare Organization of Ardabil Province, Ardabil, Iran.
authors: Fariba
authors: F
authors: Maqsoud
authors: Welfare Organization of Ardabil Province, Ardabil, Iran.
authors: Reza
authors: R
authors: Farajollahi
authors: Department of Human Molecular Genetics, Max-Plank Institute for Molecular Genetics, Berlin, Germany.
authors: Thomas F
authors: TF
authors: Wienker
authors: Department of Human Molecular Genetics, Max-Plank Institute for Molecular Genetics, Berlin, Germany.
authors: H Hilger
authors: HH
authors: Ropers
authors: Genetics Research Center (GRC), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors: Hossein
authors: H
authors: Najmabadi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001931:Brain Mapping; D002648:Child; D002675:Child, Preschool; D020090:Chromosome Segregation / Q000235:genetics; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007492:Iran; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult; D012359:tRNA Methyltransferases / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D012359:tRNA Methyltransferases