Intellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors for ...ID are malnutrition, cultural deprivation, poor health care, and parental consanguinity. In the Western world, fetal alcohol exposure is the most common preventable cause. Most severe forms of ID have genetic causes. Cytogenetically detectable and submicroscopic chromosomal rearrangements account for approximately 25% of all cases. X-linked gene defects are responsible in 10-12% of males with ID; to date, 91 of these defects have been identified. In contrast, autosomal gene defects have been largely disregarded, but due to coordinated efforts and the advent of next-generation DNA sequencing, this is about to change. As shown for Fra(X) syndrome, this renewed focus on autosomal gene defects will pave the way for molecular diagnosis and prevention, shed more light on the pathogenesis of ID, and reveal new opportunities for therapy.
Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for ...mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.
Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are ...mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.
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.
With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have ...a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T p.Gln227∗ and c.1114C>T p.Gln372∗, as well as one splicing mutation, g.6622224A>C p.Ile179Argfs∗192) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.
N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly ...Ca2+-permeable cation channels which are blocked by extracellular Mg2+ in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2AN615K (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg2+ block and a decrease in Ca2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
The advent of high‐throughput sequencing technologies has led to an exponential increase in the identification of novel disease‐causing genes in highly heterogeneous diseases. A novel frameshift ...mutation in CNKSR1 gene was detected by Next‐Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen‐activated protein kinase (MAPK) cascades. CNKSR1 interacts with proteins which have already been shown to be associated with intellectual disability (ID) in the MAPK signaling pathway and promotes cell migration through RhoA‐mediated c‐Jun N‐terminal kinase (JNK) activation. Lack of CNKSR1 transcripts and protein was observed in lymphoblastoid cells derived from affected patients using qRT–PCR and western blot analysis, respectively. Furthermore, RNAi‐mediated knockdown of cnk, the CNKSR1 orthologue in Drosophila melanogaster brain, led to defects in eye and mushroom body (MB) structures. In conclusion, our findings support the possible role of CNKSR1 in brain development which can lead to cognitive impairment.
The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3-sialyltransferase-III ...that in humans predominantly forms the sialyl Lewis a epitope on proteins. ST3GAL3 resides on chromosome 1 within the MRT4 locus previously identified to associate with nonsyndromic autosomal recessive intellectual disability. We searched for the disease-causing mutations in the MRT4 family and a second independent consanguineous Iranian family by using a combination of chromosome sorting and next-generation sequencing. Two different missense changes in ST3GAL3 cosegregate with the disease but were absent in more than 1000 control chromosomes. In cellular and biochemical test systems, these mutations were shown to cause ER retention of the Golgi enzyme and drastically impair ST3Gal-III functionality. Our data provide conclusive evidence that glycotopes formed by ST3Gal-III are prerequisite for attaining and/or maintaining higher cognitive functions.
The S‐Phase Cyclin A Associated Protein In The ER (SCAPER) gene is a ubiquitously expressed gene with unknown function in the brain. Recently, biallelic SCAPER variants were described in four ...patients from three families with retinitis pigmentosa (RP) and intellectual disability (ID). Here, we expand the spectrum of pathogenic variants in SCAPER and report on 10 further patients from four families with ID, RP, and additional dysmorphic features carrying homozygous variants in SCAPER. The variants found comprise frameshift, nonsense, and missense variants as well as an intragenic homozygous deletion, which spans SCAPER exons 15 and 16 and introduces a frameshift and a premature stop codon. Analyses of SCAPER expression in human and mouse brain revealed an upregulation of SCAPER expression during cortical development and a higher expression of SCAPER in neurons compared to neural progenitors. In the adult brain SCAPER is expressed in several regions including the cerebral cortex where it shows a layer‐specific expression with an expression peak in lower layer glutamatergic neurons. Our study supports the role of SCAPER variants in the pathogenesis of ID and RP, expands the variant spectrum and highlights the need for functional studies concerning the role of SCAPER during brain development and function.
Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs ...to the aetiology of schizophrenia (SZ). Whole-genome, high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.
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