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Identification of a Novel PAFAH1B1 Missense Mutation As a Cause Of Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev Original article Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification Chang-he Shi a,1, Shuo Zhang a,b,1, Zhi-hua Yang a,1, Yu-sheng Li a, Yu-tao Liu a, Zhuo Li a, Zheng-wei Hu a,b, Yu-ming Xu a,⇑ a Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000 Henan, China b Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China Received 14 April 2018; received in revised form 8 July 2018; accepted 17 July 2018 Abstract Purpose: To investigate the genetic and clinical features of a Chinese family exhibiting an autosomal dominant inheritance pat- tern of lissencephaly. Methods: Clinical examinations and cranial imaging studies were performed for all members of the family (two unaffected mem- bers and three surviving members from a total of four affected members). In addition, whole-exome sequencing analysis was per- formed for DNA from an affected patient to scan for candidate mutations, followed by Sanger sequencing to verify these candidate mutations in the entire family. A total of 200 ethnicity-matched healthy controls without neuropsychiatric disorder were also included and analyzed. Results: We identified a novel missense mutation, c.412G > A, p.(E138K), that cosegregated with the disease in exon 6 of the platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1) gene in the affected members; this mutation was not found in the 200 controls. Multiple sequence alignments showed that codon 138, where the mutation (c.G412A) occurred, was located within a phylogenetically conserved region. Brain magnetic resonance imaging revealed calcification within the bilateral globus pallidus in all three affected members. Conclusions: We identified a novel missense mutation, c.412G > A, p.(E138K), in the PAFAH1B1 gene of a Chinese family with lissencephaly. In addition, our findings suggest that basal ganglia calcification is a novel clinical feature of PAFAH1B1-related lissencephaly. Ó 2018 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Keywords: Lissencephaly; PAFAH1B1; Missense mutation; Basal ganglia calcification 1. Introduction brain malformation caused by impaired neuroblast migration during embryonic development due to muta- Lissencephaly, which includes classical lissencephaly tions in various genes associated with neuronal migra- (LIS) and subcortical band heterotopia (SBH), is a rare tion, such as LIS1, DCX, RELN, ARX, and YWHAE [1,2]. Patients with lissencephaly are characterized by a smooth cerebral surface, intellectual disability, and sei- ⇑ Corresponding author at: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 zures [3]. LIS presents with a four-layered and thickened Jian-she East Road, Zhengzhou 450000, Henan, China. cortex with decreased gyration [4], while SBH is a E-mail address: [email protected] (Y.-m. Xu). related disorder wherein abnormal neuroblast migration 1 The authors contributed equally to this work. https://doi.org/10.1016/j.braindev.2018.07.009 0387-7604/Ó 2018 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Please cite this article in press as: Shi C-h et al. Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.07.009 2 C.-h. Shi et al. / Brain & Development xxx (2018) xxx–xxx results in the formation of a band of heterotopic gray with the Hiseq2000 platform (Illumina, San Diego, matter between the cortex and ventricular walls, with CA, USA). Sequence data were mapped onto the hg19 an overlying six-layered cortex exhibiting shallow sulca- human genome, used as a reference, with Burrows tion [4]. Wheeler Aligner (BWA) and SAMTOOLS [13]; calls The platelet activating factor acetylhydrolase 1b regu- with a variant quality of less than 20 were filtered out, latory subunit 1 (PAFAH1B1; NM_000430.3) gene and 95% of the targeted bases were sufficiently covered encodes a 45-kDa protein designated as LIS1 or to pass our thresholds for calling single-nucleotide poly- PAFAH1B1, which exhibits an N-terminal homodimer- morphisms (SNPs) and small indels. The remaining vari- ization domain and seven C-terminal tryptophan aspar- ants were annotated using ANNOVAR, the details of tic acid 40 repeats [5,6]. PAFAH1B1 binds to which are described in previous studies [14,15]. cytoplasmic dynein, a microtubule minus end-directed motor protein, and plays a key role in cell division and 4. Polymerase chain reaction (PCR) and Sanger motility [7]. Research in mice suggests that PAFAH1B1 sequencing is necessary for nuclear movement during neuronal migration [8]. The majority of described mutations in On the basis of the results of exome sequencing, San- PAFAH1B1 are deletions, splice site mutations, and non- ger sequencing was performed to verify the identified sense mutations. Missense mutations reportedly account genetic defects. Primers flanking the mutation area in for <20% of all PAFAH1B1 mutations [9,10]. Till date, PAFAH1B1 (NM_000430.3) were designed on the basis missense mutations have been described to result in mild of reference genomic sequences in the human genome lissencephaly phenotypes and SBH [3,11]. Furthermore, obtained from GenBank at the National Center for Bio- no studies have reported calcification within the bilateral logical Information (NCBI) and synthesized by Sangon, globus pallidus in patients with lissencephaly. Shanghai, China. The forward primer was 50-CTGAGA The aim of the present study was to investigate the CAGGGAGCGGACTATG-30 and the reverse primer genetic and clinical features of a Chinese family exhibit- was 50-GCAGAACAGGAAGCCAGAAGC-30. PCR ing an autosomal dominant inheritance pattern of LIS amplification and subsequent DNA sequencing were with seizures, severe intellectual disability, and calcifica- performed. Sequence data comparisons and analyses tion within the bilateral globus pallidus. were performed using CHROMS software. Cosegrega- tion analysis was subsequently performed for the 2. Material and methods DNA samples from available family members. 2.1. Subjects and ethics approval 5. Bioinformatics analysis A three-generation family comprising two unaffected DNA sequencing results were compared with the members (I:1 and II:1) and four affected members (I:2, human reference sequence (GRCh37/hg19) using the II:2, III:1 and III:2) with LIS characterized by seizures BLAT tool from the UCSC Genome Browser. The Sin- and mental retardation was recruited for this study. gle Nucleotide Polymorphism Database, 1000 Genome Blood samples were obtained from all participants, project database, ExAC (http://exac.broadinstitute. who also underwent cranial magnetic resonance imaging org), dbSNP build 132, Hapmap, YH project, and the (MRI) studies. The severity of LIS was graded using an National Heart, Lung, and Blood Institute Exome established system [10,12]. A total of 200 ethnicity- Sequencing Project were used for the mutation exclusion matched healthy controls without neuropsychiatric dis- analysis. Four online bioinformatics tools were used for order were also included. Genomic DNA was extracted the analysis of missense mutations; Mutation Taster using the QIA-amp DNA Blood Mini Kit (QIAGEN, (http://www.mutationtaster.org), Polyphen-2 (http://ge- Germany) according to the manufacturer’s protocol. netics.bwh.harvard.edu/pph2/), and SIFT (http://sift. This study was approved by the Ethics Committee of jcvi.org) were used to predict the biological impact of the First Affiliated Hospital of Zhengzhou University, the variant in silicon, while I-Mutant (http://folding.bio- China. Written informed consent to participate in the fold.org/i-mutant/) was used to predict protein stability. study was obtained from all subjects. The closest homologs of the PAFAH1B1 protein were aligned using the program Clustal-X. 3. Whole-exome sequencing 6. Results The proband in the family was selected for exome sequencing. Targeted exon enrichment was performed 6.1. Clinical features using the SureSelect Human All Exon V4 (Agilent Tech- nologies, Santa Clara, CA, USA). The exon-enriched We initially observed a lissencephaly pedigree consis- DNA libraries were subjected to paired-end sequencing tent with an autosomal dominant inheritance pattern Please cite this article in press as: Shi C-h et al. Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.07.009 C.-h. Shi et al. / Brain & Development xxx (2018) xxx–xxx 3 and identified four affected members across three gener- brain was normal. However, she exhibited severe intel- ations (Fig. 1A). However, one of the four affected lectual disability and could only perform simple manual members was deceased, and the remaining three were tasks that did not require any skills. Furthermore, she available for analyses. needed supervision for seizures during some activities. The proband (III-1) was born at 38 weeks of gesta- Cognitive impairment was remarkable, and she was tion after a normal pregnancy. She developed symptoms unable to cope in the intelligence test. Her epilepsy at the age of 6 years, following the onset of seizures with was well controlled with carbamazepine and piracetam. episodes of confusion
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