DOCSLIB.ORG

The Molecular Landscape of ASPM Mutations in Primary Microcephaly

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Molecular Landscape of ASPM Mutations in Primary Microcephaly Original article J Med Genet: first published as 10.1136/jmg.2008.062380 on 21 November 2008. Downloaded from The molecular landscape of ASPM mutations in primary microcephaly A K Nicholas,1 E A Swanson,2 J J Cox,1 G Karbani,3 S Malik,3 K Springell,4 D Hampshire,4 M Ahmed,3 J Bond,4 D Di Benedetto,5 M Fichera,5 C Romano,6 W B Dobyns,2 C G Woods1 c Additional tables are ABSTRACT also a diagnosable cause of mental retardation, and published online only at http:// Background: Autosomal recessive primary microcephaly one with a substantial recurrence risk of one in jmg.bmj.com/content/vol46/ (MCPH) is a model disease to study human neurogenesis. issue4 four in subsequent children. In affected individuals the brain grows at a reduced rate 1 The current diagnostic criteria for MCPH are: Department of Medical during fetal life resulting in a small but structurally normal congenital microcephaly more than 23 SD below Genetics, Cambridge Institute for Medical Research, University brain and mental retardation. The condition is genetically age and sex means; mental retardation but no of Cambridge, Cambridge, UK; heterogeneous with mutations in ASPM being most other neurological finding, such as spasticity, 2 University of Chicago, commonly reported. seizures, or progressive cognitive decline; normal Department of Human Genetics, Methods and results: We have examined this further by height and weight, appearance, and results on Chicago, Illinois, USA; studying three cohorts of microcephalic children to extend 6 3 Department of Clinical chromosome analysis and brain scan. Despite this, Genetics, St James’s University both the phenotype and the mutation spectrum. Firstly, in MCPH still remains a clinical diagnosis of exclu- Hospital, Leeds, UK; 4 Section of 99 consecutively ascertained consanguineous families sion. Further, the recurrence risk of the MCPH Ophthalmology and with a strict diagnosis of MCPH, 41 (41%) were phenotype after one affected child (with careful Neuroscience, Leeds Institute of homozygous at the MCPH5 locus and all but two families Molecular Medicine, University elimination of differential diagnoses) in a non- of Leeds, Leeds, UK; had mutations. Thus, 39% of consanguineous MCPH consanguineous family is one in eight, and in a 5 Laboratory of Genetic families had homozygous ASPM mutations. Secondly, in consanguineous family one in six.7–9 Our first aim Diagnosis, I.R.C.C.S. 27 non-consanguineous, predominantly Caucasian families in designing this study was to be able to diagnose Associazione Oasi Maria with a strict diagnosis of MCPH, 11 (40%) had ASPM MCPH with greater accuracy, particularly at an Santissima, Troina (EN), Italy; mutations. Thirdly, in 45 families with a less restricted 6 Unit of Paediatrics and Medical early age, and to examine if the current diagnostic Genetics, I.R.C.C.S. phenotype including microcephaly and mental retardation, criteria accurately reflect the phenotypic spectrum Associazione Oasi Maria but regardless of other neurological features, only 3 (7%) of the disorder. Santissima, Troina (EN), Italy had an ASPM mutation. This report contains 27 novel MCPH can be caused by recessive mutations in mutations and almost doubles the number of MCPH up to seven genes.46 Unexpectedly most of the Correspondence to: associated ASPM mutations known to 57. All but one of Dr C G Woods, Department of known MCPH genes, CDK5RAP2, ASPM and Medical Genetics, Cambridge the mutations lead to the use of a premature termination 10 CENPJ (better known as CPAP ), encode centro- http://jmg.bmj.com/ Institute for Medical Research, codon, 23 were nonsense mutations, 28 deletions or somal proteins, highlighting the importance of the University of Cambridge, insertions, 5 splicing, and 1 was a translocation. Cambridge, CB2 0XY, UK; centrosome in neurogenesis.3 11–13 Despite this, a Seventeen of the 57 mutations were recurrent. There [email protected] common mechanism explaining the role of the were no definitive missense mutations found nor was MCPH genes in neurogenesis has yet to emerge. All there any mutation/phenotype correlation. ASPM muta- Received 5 August 2008 four known MCPH proteins are also present in the Revised 8 October 2008 tions were found in all ethnic groups studied. Accepted 16 October 2008 Conclusion: This study confirms that mutations in ASPM midbody (the microtubular structure linking Published Online First are the most common cause of MCPH, that ASPM daughter cells at the final stage of cytokinesis) on September 30, 2021 by guest. Protected copyright. 21 November 2008 mutations are restricted to individuals with an MCPH and have apparently diverse roles: microcephalin in phenotype, and that ASPM testing in primary micro- DNA repair and chromosome condensation, cephaly is clinically useful. CDK5RAP2 and CENPJ in centriole/centrosome replication, and ASPM in modulating the plane of cytokinesis in neural precursors.14–19 Mutations in Our most defining feature as a species is our brain the ASPM gene at the MCPH5 locus on chromo- with its large size and cognitive functions leading some 1q31.3 have been considered the most 62021 to our great adaptability.1 Many genes are involved common cause of MCPH. Our second aim in in the growth of the developing human brain but this study was to determine the frequency of the identification of those which have a non- ASPM mutations in microcephalic individuals, redundant and crucial role has proved difficult. delineate the spectrum of mutations seen in the Autosomal recessive primary microcephaly ASPM gene, and evaluate the utility of sequencing (MCPH) has emerged as a model disorder in which this gene in clinical practice. to seek such genes, as it is a condition where fetal The primary feature of MCPH is microcephaly— brain growth is significantly reduced (as is head a reduced occipitofrontal head circumference size throughout life), brain architecture is normal, (OFC)—which is an imperfect indicator of micro- and there are no apparent abnormalities in other encephaly (a small brain). Ideally volumetric body systems.2–4 Therefore the genes that cause magnetic resonance imaging (MRI) studies should This paper is freely available online under the BMJ Journals MCPH may be expected to have an important, be performed to quantitate brain volume, but this unlocked scheme, see http:// noticeable and non-redundant role in neurogenesis, is not available in current clinical practice, whereas jmg.bmj.com/info/unlocked.dtl but not other developmental processes.5 MCPH is head circumference charts are tried, tested and J Med Genet 2009;46:249–253. doi:10.1136/jmg.2008.062380 249 Original article J Med Genet: first published as 10.1136/jmg.2008.062380 on 21 November 2008. Downloaded from useful.22–24 The choice of a cut-off value for microcephaly is mutations found were shown to segregate faithfully in the important but arbitrary. Half of mentally retarded individuals family, although the degree of intrafamilial microcephaly varied, are microcephalic725and half of children with OFC of 22SDor as previously reported.6 less have normal intelligence.26 To define microcephaly some authors use an OFC ,2 SD below the mean for age and sex, RESULTS which results in 2% of the general population being considered microcephalic.27 28 Others use ,3 SD so that 0.1% of the general Of the consanguineous families in cohort 1, homozygous ASPM population are microcephalic and most do have mental mutations were found in 39/41 of families (95% of families that retardation. 72429 Added to this are probable ethnic variations were homozygous at the MCPH5 locus, 39% of all consangui- and differences in norms between growth charts. Because of all neous families). Of the families that were homozygous at the of these considerations we use an OFC of more than 23SDto MCPH5 locus with no ASPM mutations, one had a singleton define microcephaly in this study, realising that it could exclude affected child and one had an affected pair of first cousins. In a small number of true microcephalics but by corollary be cohort 2, of non-consanguineous, predominantly Caucasian unlikely to include people with normal brain volumes or individuals, ASPM mutations were found in 11/27 families intelligence. (40%), and in 3/5 sib pairs. In this cohort 19 mutations were found: four were present in other cohorts, all but one led to a premature termination codon and no novel missense mutations METHODS were found. In three families the ASPM mutation was Three cohorts of microcephalic individuals were investigated. homozygous and the remainder were compound heterozygotes. The first cohort (cohort 1) is of 99 consecutively ascertained In cohort 3, of 45 microcephalic individuals with a wider consanguineous families of Pakistani or Arab origin seen by one phenotype we found mutations in three families (7%). One author (CGW), the first 56 of which have been previously partly consanguineous and one non-consanguineous singleton each 6 reported. Seventy-three families had multiple affected members had a homozygous nonsense mutation. Both of these homo- and 26 consisted of a singleton child. No family was more zygous mutations were present in other cohorts. A child from a distantly related than parents being second cousins. All fulfilled third family carried two heterozygous protein truncating the current MCPH diagnostic criteria, with the exception that a mutations. The mutations from all three cohorts and all brain MRI scan was only available in eight families (all showed previously reported mutations are described in table 1 and no architectural anomalies). The second cohort (cohort 2) is of shown in fig 1. 27 non-consanguineous MCPH families of predominantly European origin, including five sib pairs. All had a normal brain scan and conformed to standard MCPH diagnostic criteria. The DISCUSSION third cohort (cohort 3) is of 45 children (from 45 families) that This work brings the total number of different ASPM mutations was examined specifically to answer the questions, ‘‘Are the reported to 57.
Load more

Recommended publications
  • A Nonsense (C.3978G>A) Abnormal Spindle-Like, Microcephaly Associated (ASPM) Gene Mutation Is a Major Cause of Primary Microc
    African Journal of Biotechnology Vol. 10(34), pp. 6396-6400, 11 July, 2011 Available online at http://www.academicjournals.org/AJB DOI: 10.5897/AJB10.2571 ISSN 1684-5315 © 2011 Academic Journals Full Length Research Paper A nonsense (c.3978G>A) abnormal spindle-like, microcephaly associated (ASPM) gene mutation is a major cause of primary microcephaly in Pashtoon ethnic group of Pakistan Shamim Saleha 1, Muhammad Ajmal 2, Muhammad Jamil 1, Muhammad Nasir 2 and Abdul Hameed 2* 1Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat 26000, Khyber Paktoonkhwa, Pakistan. 2Institute of Biomedical and Genetic Engineering, G.P.O. box 2891, 24-Mauve Area, G-9/1, Islamabad, Pakistan. Accepted 29 April, 2011 Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller- than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1 to MCPH7. The abnormal spindle-like, microcephaly associated (ASPM) gene at MCPH5 locus, which accounts for 37 to 54% of MCPH, appears to be the most common cause of microcephaly. More than 50% of the MCPH families genetically analyzed in Pakistan were mapped to MCPH5 locus including both families in this study. On mutation screening of ASPM gene by PCR amplification and direct DNA sequencing, a common c.3978G>A transition was identified in exon 17 of ASPM gene to be responsible for diseased phenotype in both families. This change results to the substitution of an amino acid residue at position 1326 from tryptophan to a stop codon (p.Trp1326Stop). The same mutation was also identified in several other families of Pakistani origin.
    [Show full text]
  • Molecular Genetics of Microcephaly Primary Hereditary: an Overview
    brain sciences Review Molecular Genetics of Microcephaly Primary Hereditary: An Overview Nikistratos Siskos † , Electra Stylianopoulou †, Georgios Skavdis and Maria E. Grigoriou * Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece; [email protected] (N.S.); [email protected] (E.S.); [email protected] (G.S.) * Correspondence: [email protected] † Equal contribution. Abstract: MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate. Keywords: microcephaly; MCPH; MCPH1–MCPH27; molecular genetics; cell cycle 1. Introduction Citation: Siskos, N.; Stylianopoulou, Microcephaly, from the Greek word µικρoκεϕαλi´α (mikrokephalia), meaning small E.; Skavdis, G.; Grigoriou, M.E. head, is a term used to describe a cranium with reduction of the occipitofrontal head circum- Molecular Genetics of Microcephaly ference equal, or more that teo standard deviations
    [Show full text]
  • (ASPM) Gene in an Iranian Patient with Primary Microcephaly: a Case Report
    Iran J Public Health, Vol. 48, No.11, Nov 2019, pp.2074-2078 Case Report A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report Afsaneh BAZGIR, Mehdi AGHA GHOLIZADEH, Faezeh SARVAR, *Zahra PAKZAD Department of Medical Genetics, Fardis Central Lab, Alborz, Iran *Corresponding Author: Email: [email protected] (Received 10 Mar 2019; accepted 11 Jul 2019) Abstract Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents mo- lecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families. Keywords: Autosomal recessive primary microcephaly; ASPM; Whole exome sequencing Introduction Autosomal recessive primary microcephaly ants that resulting in frameshift and protein- (MCPH) is a genetically heterogeneous condition truncating.
    [Show full text]
  • Gene List of the Targeted NGS MCD and CCA Gene Panel AKT3,ALX1
    Gene List of the targeted NGS MCD and CCA gene panel AKT3,ALX1,ALX3,ALX4,AMPD2,ARFGEF2,ARID1B,ARX,ASPM,ATR,ATRX,B3GALTL,BRPF1,c12orf57,C6orf70,CASK,CCND2,CDK5RAP2,CDON,C ENPJ,CEP170,CHMP1A,COL4A1,CREBBP,CYP11A1,DCHS1,DCLK1,DCX,DHCR24,DHCR7,DIS3L2,DISC1,DISP1,DLL1,DMRTA2,DYNC1H1,DYRK1 A,EARS2,EFNB1,EMX1,EOMES,EP300,ERBB4,ERMARD,EXOSC3,FAM36A,FGF8,FGFR1,FGFR2,FLNA,FOXC1,FOXG1,FOXH1,FZD10,GLI2,GLI3,GP R56,GPSM2,HCCS,HESX1,HNRNPU,IGBP1,IGFBP1,ISPD,ITPA,KAL1,KAT6B,KATNB1,KIAA1279,KIF14,KIF1A,KIF1B,KIF21A,KIF2A,KIF5C,KIF7,L1 CAM,LAMB1,LAMC3,LRP2,MCPH1,MED12,MID1,NDE1,NFIB,NPC1,NR2F1,NSD1,NTRK1,NTRK3,OCEL1,OPA1,OTX2,PAFAH1B1,PAX6,PEX1,PHF1 0,PIK3R2,POLR3A,POLR3B,POMT1,POMT2,PTCH1,PTPRS,PYCR1,RAB3GAP1,RARS2,RELN,RFX3,ROBO1,ROBO3,RPS6KA3,RTTN,SATB2,SEPSEC S,SHH,SIX3,SLC12A6,SOX2,SPOCK1,SRPX2,TBCD,TBCE,TCF4,TDGF1,TEAD1,THBS2,TMEM5,TSC1,TSC2,TSEN15,TSEN2,TSEN34,TSEN54,TUBA1 A,TUBA8,TUBB,TUBB2A,TUBB2B,TUBB3,TUBB4A,TUBG1,VAX1,VRK1,WDR47,WDR62,ZBTB18,ZEB2,ZIC2. Gene List of the targeted NGS epilepsy gene panel AARS, ADGRV1, ADRA2B, ADSL, ALDH4A1, ALDH7A1, ALG13, ALPL, ARHGEF15, ARHGEF9, ARX, ASAH1, ATP1A2, ATP1A3, BRD2, CACNA1A, CACNA1H, CACNA2D2, CACNB4, CBL, CDKL5, CERS1, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN2, CLCN4, CLN8, CLTC, CNKSR2, CNTNAP2, CPA6, CPLX1, CSNK1G1, CSNK2B, CTNND2, DEPDC5, DHDDS, DNM1, DOCK7, DYNC1H1, EEF1A2, EFHC1, EIF2S3, EMC1, EPM2A, FASN, FLNA, FOXG1, GABBR2, GABRA1, GABRA2, GABRA3, GABRB2, GABRB3, GABRD, GABRG2, GAL, GNAO1, GOSR2, GRIA1, GRIN1, GRIN2A, GRIN2B, HCN1, HCN4, HDAC4, HNRNPU, IDH3A, IQSEC2, JRK, KCNA1, KCNA2, KCNB1,
    [Show full text]
  • Supplementary Information
    Osa et al Supplementary Information Clinical implications of monitoring nivolumab immunokinetics in previously treated non– small cell lung cancer patients Akio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa, Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra A. Akbay, Peter S. Hammerman, Kwok-kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, Atsushi Kumanogoh Supplemental Figures 1 – 8 1 Osa et al Supplemental Figure 1. The frequency of nivolumab-bound T cells was maintained in patients who continued treatment. Nivolumab binding in CD8 and CD4 T cells was analyzed at two follow-up points, as indicated, in fresh peripheral blood from three representative cases from protocol 1 that continued treatment. 2 Osa et al Supplemental Figure 2. Long-term follow-up of nivolumab binding to T cells from fresh whole blood. Nivolumab binding was followed up in fresh peripheral blood from an additional case, Pt.7. 3 Osa et al Supplemental Figure 3. Long-term duration of nivolumab binding is due to sustained circulation of residual nivolumab in plasma. (A) PBMCs acquired from Pt.8 and 9 at pretreatment (pre PBMCs) and after a single dose (post 1 PBMCs) were cultured in regular medium without nivolumab (top and middle). Pre PBMCs were also incubated with 10 µg/ml nivolumab in vitro before the cultures were started (bottom). Nivolumab binding status was monitored at the indicated time points.
    [Show full text]
  • Markers of Clinical Utility in the Differential Diagnosis and Prognosis of Prostate Cancer Glen Kristiansen
    Modern Pathology (2018) 31, S143–S155 © 2018 USCAP, Inc All rights reserved 0893-3952/18 $32.00 S143 Markers of clinical utility in the differential diagnosis and prognosis of prostate cancer Glen Kristiansen Institute of Pathology of the University Hospital Bonn, Bonn, Germany Molecular diagnostics is a rapidly evolving area of surgical pathology, that is gradually beginning to transform our diagnostical procedures for a variety of tumors. Next to molecular prognostication that has begun to complement our histological diagnosis in breast cancer, additional testing to detect targets and to predict therapy response has become common practice in breast and lung cancer. Prostate cancer is a bit slower in this respect, as it is still largely diagnosed and classified on morphological grounds. Our diagnostic immunohis- tochemical armamentarium of basal cell markers and positive markers of malignancy now allows to clarify the majority of lesions, if applied to the appropriate morphological context (and step sections). Prognostic immunohistochemistry remains a problematic and erratic yet tempting research field that provides information on tumor relevance of proteins, but little hard data to integrate into our diagnostic workflow. Main reasons are various issues of standardization that hamper the reproducibility of cut-off values to delineate risk categories. Molecular testing of DNA-methylation or transcript profiling may be much better standardized and this review discusses a couple of commercially available tests: The ConfirmDX test measures DNA-methylation to estimate the likelihood of cancer detection on a repeat biopsy and may help to reduce unnecessary biopsies. The tests Prolaris, OncotypeDX Prostate, and Decipher all are transcript tests that have shown to provide prognostic data independent of clinico-pathological parameters and that may aid in therapy planning.
    [Show full text]
  • New Experimental Evidence and Its Consequences for Linguistics
    Genetic influences on tone? New experimental evidence and its consequences for linguistics. Dan Dediu1* and D. Robert Ladd2 1 Laboratoire Dynamique Du Langage UMR 5596, Université Lumière Lyon 2, Lyon, France 2 Linguistics and English Language, The University of Edinburgh, Edinburgh, UK * Corresponding author: [email protected] Abstract: In 2007, we used a cross-linguistic statistical analysis to show that there seems to be a negative correlation between the population frequency of the “derived” alleles of two genes involved in brain growth and development, ASPM and Microcephalin (or MCHP1), and the use of tone in the language(s) spoken by the population. Despite our best attempts at disentangling the confounding effects of contact and genealogical inheritance, and the fact that these correlations stood out among millions of similar correlations between multiple genetic markers and linguistic features, this was, at best, a statistical association and, at worst, a false positive. However, new experimental evidence has recently been published independently of us, showing that the negative correlation between the “derived” allele of ASPM and tone perception and/or processing is present at the level of inter-individual differences among more than 400 native speakers of Cantonese, providing strong support for our initial findings (on the other hand, there is no signal for MCPH1). Here we contextualize and summarize these experimental findings, we address some remaining puzzles (including MCHP1 and the absence of tone in Australia), and we discuss the implications of these results for the language sciences. Genes & tone: a comment on new experimental evidence and its consequences Introduction: genetic influences on language and speech At the most general level, it is beyond debate that there is something about the human genome that makes language possible.
    [Show full text]
  • Real and Spurious Correlations Involving Tonal Languages Jeremy Collins Radboud University, Nijmegen
    Chapter 10 Real and spurious correlations involving tonal languages Jeremy Collins Radboud University, Nijmegen Why are some languages tonal? Is there a fundamental reason why some lan- guages develop tone and others do not, and and does this have an effect on the way the rest of the language is organized? Tone is important in the context of dependencies, because there is no shortage of hypotheses about what can cause tone and what else tone can cause. For example, tonal languages are found pre- dominantly in warm, humid climates, suggesting that they are culturally adap- tive in those environments (Everett, Blasi & Roberts 2015); they are also found in places with low frequencies of two genes microcephalin and ASPM, suggesting that some populations are more likely to use tone than others because of their genetics (Dediu & Ladd 2007). One paper furthermore proposed that phoneme diversity declines with distance from Africa, and number of tones in particular, suggesting a founder effect of migrations, as well as a link with modern popula- tion size (Atkinson 2011). As for effects on the rest of the language, SVOword order (Yiu & Matthews 2013) and various other grammatical properties have been suggested to linked functionally with tone, and by Donegan & Stampe (1983) in particular for languages in the Austro-Asiatic family. At least part of the reason for the large number of correlations proposed in the literature is the visibly skewed geographical distribution of tonal languages (Fig- ure 1). They are predominantly found in Africa and Southeast Asia, immediately suggesting that tone will correlate with a large number of things, from humid climates and SVO languages, to serial verbs, and ancient settlement.
    [Show full text]
  • Primary Microcephaly Caused by Novel Compound Heterozygous Mutations in ASPM
    OPEN Citation: Human Genome Variation (2018) 5, 18015; doi:10.1038/hgv.2018.15 Official journal of the Japan Society of Human Genetics www.nature.com/hgv DATA REPORT Primary microcephaly caused by novel compound heterozygous mutations in ASPM Nobuhiko Okamoto1,3, Tomohiro Kohmoto2,3, Takuya Naruto2, Kiyoshi Masuda2 and Issei Imoto2 Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified. Human Genome Variation (2018) 5, 18015; doi:10.1038/hgv.2018.15; published online 5 April 2018 Autosomal recessive primary microcephaly (microcephaly primary recognition and ability to communicate with others developed hereditary, MCPH, MIM#251200) is a genetically heterogeneous slowly. Routine laboratory investigations and metabolic surveys developmental disorder that is characterized by prenatal onset of revealed normal results. Standard karyotyping and array-based abnormal brain growth, resulting in a reduced brain volume, comparative genomic hybridization using peripheral blood which is indirectly measured as an occipitofrontal circumference revealed no abnormalities. His body weight at 8 years of age (OFC) that is equal to or greater than 2 standard deviations (SDs) was 12.5 kg (−1.8 SD), height was 90 cm (−3.0 SD) and OFC was and 3 SDs below the age- and sex-matched means at birth and 41.5 cm (−5.2 SD).
    [Show full text]
  • Human Microcephaly ASPM Protein Is a Spindle Pole-Focusing Factor That Functions Redundantly with CDK5RAP2 Elsa A
    © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 3676-3684 doi:10.1242/jcs.203703 RESEARCH ARTICLE Human microcephaly ASPM protein is a spindle pole-focusing factor that functions redundantly with CDK5RAP2 Elsa A. Tungadi*, Ami Ito*, Tomomi Kiyomitsu and Gohta Goshima‡ ABSTRACT C-terminal domain, and thus postulating that Asp is a critical Nonsense mutations in the ASPM gene have been most frequently pole-focusing factor (Ito and Goshima, 2015). Recent studies have identified among familial microcephaly patients. Depletion of the also shown that asp mutant flies have reduced brain size (Rujano Drosophila orthologue (asp) causes spindle pole unfocusing during et al., 2013; Schoborg et al., 2015), which was at least partly mitosis in multiple cell types. However, it remains unknown whether attributed to the chromosome mis-segregation associated with human ASPM has a similar function. Here, by performing CRISPR- unfocused spindle poles (Rujano et al., 2013). based gene knockout (KO) and RNA interference combined with The cellular function of human ASPM has been evaluated using auxin-inducible degron, we show that ASPM functions in spindle pole RNA interference (RNAi)-mediated knockdown. Small interfering organisation during mitotic metaphase redundantly with another RNA (siRNA)-based knockdown in U2OS cells led to spindle microcephaly protein, CDK5RAP2 (also called CEP215), in human misorientation, cytokinesis failure, a reduction in the number of tissue culture cells. Deletion of the ASPM gene alone did not affect mitotic cells and apoptosis (Higgins et al., 2010), possibly through spindle morphology or mitotic progression. However, when the interactions with the citron kinase (Gai et al., 2016; Paramasivam pericentriolar material protein CDK5RAP2 was depleted in ASPM et al., 2007).
    [Show full text]
  • Regulation of Human Cerebral Cortical Development by EXOC7
    ARTICLE Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival Michael E. Coulter, MD, PhD1,2, Damir Musaev, BSc3, Ellen M. DeGennaro, BA1,4, Xiaochang Zhang, PhD1,5, Katrin Henke, PhD6, Kiely N. James, PhD3, Richard S. Smith, PhD1, R. Sean Hill, PhD1, Jennifer N. Partlow, MS1, Muna Al-Saffar, MBChB, MSc1,7, A. Stacy Kamumbu, BA1, Nicole Hatem, BA1, A. James Barkovich, MD8, Jacqueline Aziza, MD9, Nicolas Chassaing, MD, PhD10,11, Maha S. Zaki, MD, PhD12, Tipu Sultan, MD13, Lydie Burglen, MD, PhD14,15, Anna Rajab, MD, PhD16, Lihadh Al-Gazali, MBChB, MSc7, Ganeshwaran H. Mochida, MD, MMSc1,17, Matthew P. Harris, PhD6, Joseph G. Gleeson, MD3 and Christopher A. Walsh, MD, PhD 1 Purpose: The exocyst complex is a conserved protein complex that (LOF) variants in a recessively inherited disorder characterized by mediates fusion of intracellular vesicles to the plasma membrane brain atrophy, seizures, and developmental delay, and in severe and is implicated in processes including cell polarity, cell migration, cases, microcephaly and infantile death. In EXOC8, we found a ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. homozygous truncating variant in a family with a similar clinical The essential role of these genes in human genetic disorders, disorder. We modeled exoc7 deficiency in zebrafish and found the however, is unknown. absence of exoc7 causes microcephaly. Methods: We performed homozygosity mapping and exome Conclusion: Our results highlight the essential role of the exocyst sequencing of consanguineous families with recessively inherited pathway in normal cortical development and how its perturbation brain development disorders.
    [Show full text]
  • ASPM Combined with KIF11 Promotes the Malignant Progression of Hepatocellular Carcinoma Via the Wnt/Β‑Catenin Signaling Pathway
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 1154, 2021 ASPM combined with KIF11 promotes the malignant progression of hepatocellular carcinoma via the Wnt/β‑catenin signaling pathway BIN WU1, CHUNYANG HU2 and LIANBAO KONG2 1Department of General Surgery, Sir Run Run Hospital Nanjing Medical University, Nanjing, Jiangsu 211166; 2Department of Hepatological Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China Received February 20, 2021; Accepted June 14, 2021 DOI: 10.3892/etm.2021.10588 Abstract. To investigate the molecular mechanism of assembly interact with KIF11 in HCC cells to promote the malignant factor for spindle microtubules (ASPM) in the regulation of progression of HCC via the Wnt/β‑catenin signaling pathway. the malignant progression of hepatocellular carcinoma (HCC), bioinformatics analysis was utilized to analyze the role of Introduction ASPM in the malignant progression of HCC and its potential interaction with the kinesin family member 11 (KIF11) gene. Liver cancer is one of the most common causes of cancer‑asso‑ The expression levels of ASPM and KIF11 were detected by ciated mortality worldwide, with the fifth highest incidence reverse transcription‑quantitative PCR and western blotting. and mortality rates in the United States, and a continuously Following knockdown of ASPM expression, Cell Counting increasing mortality rate on an annual basis, despite the Kit‑8/colony formation assays were performed to detect cell advances in medical technology (1). Hepatocellular carcinoma viability and proliferation. Wound healing and Transwell (HCC) is the most common type of primary liver cancer, and assays were employed to detect cell migration and invasion. its occurrence has been associated with hepatitis B virus, Additionally, a co‑immunoprecipitation (CO‑IP) assay was hepatitis C virus, smoking, alcohol consumption, obesity, used to detect whether there was an interaction between ASPM diabetes and other factors (2,3).
    [Show full text]