RESUMO
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.
Assuntos
Anormalidades Múltiplas/genética , Encefalopatias/genética , Retardo do Crescimento Fetal/genética , Ictiose/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Fosfoglicerato Desidrogenase/genética , Serina/metabolismo , Alelos , Sequência de Aminoácidos , Animais , Erros Inatos do Metabolismo dos Carboidratos/genética , Cromossomos Humanos Par 1/genética , Consanguinidade , Feminino , Loci Gênicos , Homozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Mutação , Linhagem , Fenótipo , Fosfoglicerato Desidrogenase/deficiência , Fosfoglicerato Desidrogenase/metabolismo , Conformação Proteica , Transtornos Psicomotores/genética , Doenças Raras/genética , Convulsões/genética , Serina/deficiência , Ultrassonografia Pré-NatalRESUMO
A survey was conducted in Al-Kharj governorate, Riyadh region to identify viruses causing variety of virus-like symptoms on tomato plants. A total of 135 samples were collected from symptomatic tomato plants. Symptoms included mottling, deformation, necrosis of leaves and fruits. Eighteen viruses were tested by DAS-ELISA. Tomato black ring virus (TBRV) was the virus of concern as it was not detected in Saudi Arabia before and was detected in 52.6% of the collected samples in this study. RT-PCR was used to confirm detection of TBRV and to sequence the amplified products to determine molecular characteristics of this virus. In the host range test study that was performed using a purified isolate of TBRV, sixteen out of the twenty two tested plants showed symptoms. Brassica oleracea was not infected by this virus. Gel electrophoreses (2% agarose) yielded fragments of 978 bp of coat protein gene of TBRV. Nucleotide sequences of purified RT-PCR products for three TBRV Saudi isolates were deposited in the GenBank with the following accession numbers MT274656, MT274657, and MT274658. These isolates of TBRV indicated a close Phylogenetic relationship of (99-100%) among themselves and with five isolates from Poland (95-98%) but a distant relationship of 85% with isolates from England and Lithuania deposited in the GenBank. This is the first report for detection and molecular characterization of TBRV infecting tomato plants in Saudi Arabia.