A c.726C>G (p.Tyr242Ter) nonsense mutation-associated with splicing alteration (NASA) of WDR45 gene underlies β-propeller protein-associated neurodegeneration (BPAN)
Qiongling Peng,
Ying Cui,
Jin Wu,
Lianying Wu,
Jiajia Liu,
Yangyun Han,
Guanting Lu
Affiliations
Qiongling Peng
Department of Child Healthcare, Shenzhen Bao'an Women's and Children's Hospital, 56 Yulyu Road, Bao'an District, Shenzhen, 518000, China
Ying Cui
Department of Blood Transfusion, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
Jin Wu
Laboratory of Translational Medicine Research, Department of Pathology, Affiliated Deyang People's Hospital of Sichuan Traditional Medical University, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Deyang Key Laboratory of Tumor Molecular Research, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China
Lianying Wu
Laboratory of Translational Medicine Research, Department of Pathology, Affiliated Deyang People's Hospital of Sichuan Traditional Medical University, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Deyang Key Laboratory of Tumor Molecular Research, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China
Jiajia Liu
Department of Child Healthcare, Shenzhen Bao'an Women's and Children's Hospital, 56 Yulyu Road, Bao'an District, Shenzhen, 518000, China
Yangyun Han
Sichuan Clinical Medical Research Center for Neurological Diseases, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Corresponding author. Yangyun Han.
Guanting Lu
Laboratory of Translational Medicine Research, Department of Pathology, Affiliated Deyang People's Hospital of Sichuan Traditional Medical University, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Deyang Key Laboratory of Tumor Molecular Research, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Sichuan Clinical Medical Research Center for Neurological Diseases, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China; Corresponding author. Laboratory of Translational Medicine Research, Deyang People's Hospital, No. 103 First Section of Taishanbei Road, Jingyang District, Deyang, 618000, China.
Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous disease characterized by increased iron deposition in the basal ganglia and progressive degeneration of the nervous system in adulthood. However, in early childhood, there were no characteristic features to perform early diagnosis. In our study, a female child exhibited global developmental delay, intellectual disability, and febrile seizure without other distinct clinical phenotypes. Through whole exome sequencing (WES), a de novo nonsense mutation (c.726C > G, p. Tyr242Ter) of WDR45 gene was identified in this child. She was finally diagnosed as β‐propeller protein-associated neurodegeneration (BPAN), one of the recently identified subtypes of NBIA. This mutation could act as a premature stop codon (PSC) which rendered the mutated transcripts to be degraded by nonsense-mediated mRNA decay (NMD), leading to decreased levels of PSC-containing mRNAs. Additionally, through mini-gene splicing assays, this mutation could result in an unprecedented novel transcript with the exon 9 of WDR45 excluded by nonsense-associated splicing alteration (NASA). Transcriptome sequencing (RNA-seq) on total RNAs from PBMCs of the trio revealed three types of alternative splicing events in the patient. Further research implied that downregulation of iron transport genes (TFRC, TFR2, SCARA5) might be the underlying mechanism for the iron accumulation in patients with deficient WDR45. This is the first report about NASA happening in WDR45. It implies that nonsense mutations approximal to splicing sites could affect the disease pathogenesis through more than one molecular mechanism and should be taken into consideration when conducting genetic counseling.
