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Progressive microcephaly is caused by compound-heterozygous mutations in QARS References 1. Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol 2007: 14: 118–127. 2. Kaminska M, Havrylenko S, Decottignies P et al. Dissection of the structural organization of the aminoacyl-tRNA synthetase complex. J Biol Chem 2009: 284: 6053–6060. 3. Rho SB, Kim MJ, Lee JS et al. Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex. Proc Natl Acad Sci U S A 1999: 96: 4488–4493.
Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral– cerebellar atrophy, and intractable seizures Zhang et al. (2014) The American Journal of Human Genetics;94(4): 547–558.
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The term progressive microcephaly (PM) refers to a condition with diffuse cerebral–cerebellar atrophy associated with microcephaly [head circumference more than 2 standard deviation (SD) below the mean] and is often linked to defects in gene transcription or protein translation (1). In this study the authors report the occurrence of PM in four children of two unrelated families, in which neither of the parents have had any history of neurological problems. They suspect mutations in the gene QARS (encoding glutaminyl t-RNA synthetase) in all four individuals to be responsible for the phenotype. They then support their findings with in vitro studies on functionality and solubility of mutated QARS, as well as in vivo effects in qars deficient Zebrafish. Family 1 has three children of which two are affected. The two brothers, aged 5 and 4 years presented at full term with a sloping forehead and an occipitofrontal circumference (OFC) of −3.5 and −2.1 SD, respectively. Both children showed severe developmental delay and at 21 and 7 months of age, respectively, they presented with a smaller OFC (−10.4 and −7.8 SDs), height (−2.3 and −2.1 SDs) and weight (−3.8 and 2.1 SDs). They had seizure onset within the first day of life and pharmacoresistant status epilepticus (SE). The elder brother was treated with trials of various antiepileptic drugs (AED) all of which were ineffective in controlling the seizures. Between age 2 and 3 they had periods of severe illnesses marked with similar symptoms and lasting for several months but lacking the usual seizures. Family 2 has two children, both born affected and with an OFC of −1 SD. The elder brother started having seizures on the first day of life, the younger sister at 1 month of age. Both were resistant to AED. The elder brother developed microcephaly (OFC −3 SD) at 5.5 years of age, with drastic psychomotor delay. The younger sister had microcephaly (−2.5 SD) at the age of 3 years without the expected developmental skills. By 5 years of age, all four children showed neurodegeneration, hypomyelination or delayed myelination, a
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Fig. 2. Predicted domain structure of QARS. QARS variants in family 1 are indicated in blue, variants in family 2 in red.
thin corpus callosum, reduced white matter, moderately enlarged cerebral ventricles, small cerebellar vermis and a mild atrophy of the cerebellar hemispheres. The two brothers of family 1 had a more severe microcephaly. Whole-exome sequencing in the two families discovered, that mutations in the gene QARS, encoding QARS, a component of the multisynthetase complex (MSC) in human cells (2) are likely responsible for the phenotype. In fetal human cerebral cortex QARS mRNA is highly expressed in the ventricular zone, inner and outer subventricular zone and cortical plate. The two affected brothers of family 1 had separately inherited QARS mutations c.134G>T [p.Gly45Val] and c.1207C>T [p.Arg403Trp], the children of family 2 had inherited c.169T>C [p.Tyr57His] and c.1543C>T [p.Arg515Trp] (Fig. 2). The healthy child of family 1 inherited only one of these alleles. All four mutated residues are in a highly conserved region across vertebrate and plant species and are predicted to be harmful for protein function. To test functionality of mutated QARS variants, the authors tested glutamine aminoacylation activity. In lymphoblasts derived from the affected children activity was significantly impaired, whereas it was slightly impaired in cells derived from their parents. Furthermore, aminoacylation activity in vitro was completely
disrupted in two of the mutant variants (p.Arg403Trp and p.Arg515Trp), and was decreased to 10% in the N-terminal variants (p.Gly45Val and p.Tyr57His). Protein expression was normal, but the portion of insoluble QARS was increased in p.Arg403Trp and p.Arg515Trp mutations, suggesting increased protein misfolding and aggregation. The N-terminal domain of QARS has been shown to interact with RARS (arginyl-tRNA synthetase) in the MSC (3). The authors showed that this interaction was severely disrupted only in the p.Arg403Trp mutant. The authors also found that homozygous qars mutant (−/−) Zebrafish developed significantly smaller eyes and brains at 3 days post-fertilization (dpf). Starting from 3 dpf, mutant fish were smaller and less pigmented. However, significantly more apoptotic cells in brain and eyes were detected at 6 dpf suggesting that cell death occurs at later stages of development. This work by Zhang et al. shows that loss-of-function mutations in QARS lead to a syndrome presenting with PM, epilepsy and brain atrophy. S. Waltl Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected]
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Copyright of Clinical Genetics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Progressive microcephaly is caused by compound-heterozygous mutations in QARS References 1. Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol 2007: 14: 118–127. 2. Kaminska M, Havrylenko S, Decottignies P et al. Dissection of the structural organization of the aminoacyl-tRNA synthetase complex. J Biol Chem 2009: 284: 6053–6060. 3. Rho SB, Kim MJ, Lee JS et al. Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex. Proc Natl Acad Sci U S A 1999: 96: 4488–4493.
Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral– cerebellar atrophy, and intractable seizures Zhang et al. (2014) The American Journal of Human Genetics;94(4): 547–558.
508
The term progressive microcephaly (PM) refers to a condition with diffuse cerebral–cerebellar atrophy associated with microcephaly [head circumference more than 2 standard deviation (SD) below the mean] and is often linked to defects in gene transcription or protein translation (1). In this study the authors report the occurrence of PM in four children of two unrelated families, in which neither of the parents have had any history of neurological problems. They suspect mutations in the gene QARS (encoding glutaminyl t-RNA synthetase) in all four individuals to be responsible for the phenotype. They then support their findings with in vitro studies on functionality and solubility of mutated QARS, as well as in vivo effects in qars deficient Zebrafish. Family 1 has three children of which two are affected. The two brothers, aged 5 and 4 years presented at full term with a sloping forehead and an occipitofrontal circumference (OFC) of −3.5 and −2.1 SD, respectively. Both children showed severe developmental delay and at 21 and 7 months of age, respectively, they presented with a smaller OFC (−10.4 and −7.8 SDs), height (−2.3 and −2.1 SDs) and weight (−3.8 and 2.1 SDs). They had seizure onset within the first day of life and pharmacoresistant status epilepticus (SE). The elder brother was treated with trials of various antiepileptic drugs (AED) all of which were ineffective in controlling the seizures. Between age 2 and 3 they had periods of severe illnesses marked with similar symptoms and lasting for several months but lacking the usual seizures. Family 2 has two children, both born affected and with an OFC of −1 SD. The elder brother started having seizures on the first day of life, the younger sister at 1 month of age. Both were resistant to AED. The elder brother developed microcephaly (OFC −3 SD) at 5.5 years of age, with drastic psychomotor delay. The younger sister had microcephaly (−2.5 SD) at the age of 3 years without the expected developmental skills. By 5 years of age, all four children showed neurodegeneration, hypomyelination or delayed myelination, a
HotSpots
Fig. 2. Predicted domain structure of QARS. QARS variants in family 1 are indicated in blue, variants in family 2 in red.
thin corpus callosum, reduced white matter, moderately enlarged cerebral ventricles, small cerebellar vermis and a mild atrophy of the cerebellar hemispheres. The two brothers of family 1 had a more severe microcephaly. Whole-exome sequencing in the two families discovered, that mutations in the gene QARS, encoding QARS, a component of the multisynthetase complex (MSC) in human cells (2) are likely responsible for the phenotype. In fetal human cerebral cortex QARS mRNA is highly expressed in the ventricular zone, inner and outer subventricular zone and cortical plate. The two affected brothers of family 1 had separately inherited QARS mutations c.134G>T [p.Gly45Val] and c.1207C>T [p.Arg403Trp], the children of family 2 had inherited c.169T>C [p.Tyr57His] and c.1543C>T [p.Arg515Trp] (Fig. 2). The healthy child of family 1 inherited only one of these alleles. All four mutated residues are in a highly conserved region across vertebrate and plant species and are predicted to be harmful for protein function. To test functionality of mutated QARS variants, the authors tested glutamine aminoacylation activity. In lymphoblasts derived from the affected children activity was significantly impaired, whereas it was slightly impaired in cells derived from their parents. Furthermore, aminoacylation activity in vitro was completely
disrupted in two of the mutant variants (p.Arg403Trp and p.Arg515Trp), and was decreased to 10% in the N-terminal variants (p.Gly45Val and p.Tyr57His). Protein expression was normal, but the portion of insoluble QARS was increased in p.Arg403Trp and p.Arg515Trp mutations, suggesting increased protein misfolding and aggregation. The N-terminal domain of QARS has been shown to interact with RARS (arginyl-tRNA synthetase) in the MSC (3). The authors showed that this interaction was severely disrupted only in the p.Arg403Trp mutant. The authors also found that homozygous qars mutant (−/−) Zebrafish developed significantly smaller eyes and brains at 3 days post-fertilization (dpf). Starting from 3 dpf, mutant fish were smaller and less pigmented. However, significantly more apoptotic cells in brain and eyes were detected at 6 dpf suggesting that cell death occurs at later stages of development. This work by Zhang et al. shows that loss-of-function mutations in QARS lead to a syndrome presenting with PM, epilepsy and brain atrophy. S. Waltl Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected]
509
Copyright of Clinical Genetics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
