Analysis of <i><scp>ASPM</scp></i> in an ethnically diverse cohort of 400 patient samples: perspectives of the molecular diagnostic laboratory

Tan, Christopher; Gaudio, Daniela del; Dempsey, Melissa A; Arndt, Kelly; Botes, Shaun; Reeder, Amanda; Das, Soma

doi:10.1111/cge.12172

Cited by 16 publications

(19 citation statements)

References 25 publications

(39 reference statements)

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“…Although a large number of patients with ASPM mutations have been reported (Abdel‐Hamid et al., ; Ahmad et al., ; Akbariazar et al., ; Al‐Gazali & Ali, ; Ariani et al., ; Bond et al., ; Bond et al., ; Darvish et al., ; Desir, Abramowicz, & Tunca, ; Desir, Cassart, David, Van Bogaert, & Abramowicz, ; Gul et al., ; Gul et al., ; Halsall, Nicholas, Thornton, Martin, & Geoffrey Woods, ; Hashmi et al., ; Hu et al., ; Kousar et al., ; Kumar, Blanton, Babu, Markandaya, & Girimaji, ; Muhammad et al., ; Nakamura et al., ; Nicholas et al., ; Papari et al., ; Passemard et al., ; Pichon, Vankerckhove, Bourrouillou, Duprez, & Abramowicz, ; Rump et al., ; Saadi et al., ; Sajid Hussain et al., ; Shen et al., ; Tan et al., ; Wang, Khan, Han, & Zhang, ), their developmental phenotype has been documented only in a minority of cases. However, ID (Passemard et al., ) and epilepsy (Shen et al., ) are the most frequently reported clinical findings in patients with ASPM mutations.…”

Section: Introductionmentioning

confidence: 99%

Autosomal recessive primary microcephaly due to ASPM mutations: An update

et al. 2018

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Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.

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Section: Introductionmentioning

confidence: 99%

Autosomal recessive primary microcephaly due to ASPM mutations: An update

et al. 2018

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“…All novel ASPM mutations are nonsense or frameshift mutations that most probably induce nonsense‐mediated mRNA decay and thus result in a complete loss of ASPM function irrespective of the position of the mutation. The current study increases the total number of different ASPM mutations from 133 to 142 . The 142 mutations comprise 59 nonsense, 4 missense and 8 splice site mutations.…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity in Pakistani microcephaly families revisited

et al. 2017

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Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

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“…Homozygous mutations in the ASPM gene have been identified at various positions in microcephaly patients, almost all of which introduce a premature stop codon in the gene (Bond et al, 2002, Tan et al, 2014, Bond et al, 2003, Nicholas et al, 2009, Abdel-Hamid et al, 2016. The two most C-terminal mutations identified in three previous studies were located in front of the HEAT repeat motif: a nonsense mutation at amino acid (aa) 3,233 and a 1-bp deletion at aa 3,252, which introduces a stop codon at aa 3,261 ( Fig.…”

Section: Microcephaly Mutation In Aspm Causes Pole Unfocusing In the mentioning

confidence: 99%

“…The most common cause of autosomal recessive primary microcephaly is a homozygous mutation of the abnormal spindle-like microcephaly-associated (ASPM) gene (Bond et al, 2002, Tan et al, 2014, Bond et al, 2003, Abdel-Hamid et al, 2016. ASPM was originally identified in Drosophila, as the orthologue Asp (abnormal spindle), whose mutation results in abnormal spindle formation (Ripoll et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Human microcephaly ASPM protein is a spindle pole-focusing factor that functions redundantly with CDK5RAP2

Tungadi

Ito

Kiyomitsu

et al. 2017

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IntroductionThe most common cause of autosomal recessive primary microcephaly is a homozygous mutation of the abnormal spindle-like microcephaly-associated (ASPM) gene (Bond et al., 2002, Tan et al., 2014, Bond et al., 2003, Abdel-Hamid et al., 2016. ASPM was originally identified in Drosophila, as the orthologue Asp (abnormal spindle), whose mutation results in abnormal spindle formation (Ripoll et al., 1985). In the absence of Asp, centrosomes are detached from the main body of the spindle, and spindle microtubules (MTs) are unfocused at the pole (Saunders et al., 1997, Wakefield et al., 2001, Morales-Mulia and Scholey, 2005, Ito and Goshima, 2015, Schoborg et al., 2015. Asp is concentrated at the spindle pole, the area enriched with the spindle MT minus ends. The current model is that Asp binds directly to the spindle MT ends using the middle region containing calponin homology domains and cross-links them each other using the C-terminal domain, thus postulating Asp as a critical pole-focusing factor (Ito and Goshima, 2015). Recent studies have also shown that asp mutant flies have reduced brain size (Rujano et al., 2013, Schoborg et al., 2015, which was at least partly attributed to chromosome mis-segregation associated with unfocused spindle poles (Rujano et al., 2013).The cellular function of human ASPM has been evaluated using RNA interference (RNAi)-mediated knockdown. Small interfering RNA (siRNA)-based knockdown in U2OS cells led to spindle misorientation, cytokinesis failure, reduction in mitotic cells, and apoptosis (Higgins et al., 2010), possibly through interactions with the citron kinase (Gai et al., 2016, Paramasivam et al., 2007. Another study observed downregulation of BRCA1 protein upon ASPM knockdown (Zhong et al., 2005). To the best of our knowledge, the pole-focusing defect commonly observed upon Asp depletion in Drosophila has not been reported in studies of human ASPM knockdown. However, RNAi has a general limitation in that residual protein expression might suffice to fulfil the function of the target protein.Moreover, none of the previous RNAi studies of ASPM involved a rescue experiment in which full-length ASPM was ectopically expressed after endogenous ASPM depletion, leaving the possibility that some of the observed phenotypes were derived from off-target effects of the siRNAs utilised. The effect of mutations identified in microcephaly patients has also not been assessed using a cell culture model. Nevertheless, the lack of the spindle pole phenotype is surprising, given the result obtained in Drosophila.In this study, we used CRISPR/Cas9-based knockout (KO) as well as RNAi to decipher the mitotic function of ASPM in the human HCT116 cell line. Our data provide the first demonstration that human ASPM is an important factor in spindle pole organisation, working redundantly with the centrosomal protein CDK5RAP2. Furthermore, a mutation identified in microcephaly patients similarly impaired this function of ASPM. ResultsNo mitotic abnormality upon ASPM KO in the human HCT116 cell ...

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Analysis of ASPM in an ethnically diverse cohort of 400 patient samples: perspectives of the molecular diagnostic laboratory

Cited by 16 publications

References 25 publications

Autosomal recessive primary microcephaly due to ASPM mutations: An update

Autosomal recessive primary microcephaly due to ASPM mutations: An update

Genetic heterogeneity in Pakistani microcephaly families revisited

Human microcephaly ASPM protein is a spindle pole-focusing factor that functions redundantly with CDK5RAP2

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