Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Newest Articles
    • Current Issue
    • Methods & Resources
    • Archive
    • Subjects
  • Collections
  • Submit
    • Submit a Manuscript
    • Author Guidelines
    • License, Copyright, Fee
    • FAQ
    • Why Submit
  • About
    • About Us
    • Editors & Staff
    • Board Members
    • Licensing and Reuse
    • Reviewer Guidelines
    • Privacy Policy
    • Advertise
    • Contact Us
    • LSA LLC
  • Alerts
  • Other Publications
    • EMBO Press
    • The EMBO Journal
    • EMBO reports
    • EMBO Molecular Medicine
    • Molecular Systems Biology
    • Rockefeller University Press
    • Journal of Cell Biology
    • Journal of Experimental Medicine
    • Journal of General Physiology
    • Cold Spring Harbor Laboratory Press
    • Genes & Development
    • Genome Research

User menu

  • My alerts

Search

  • Advanced search
Life Science Alliance
  • Other Publications
    • EMBO Press
    • The EMBO Journal
    • EMBO reports
    • EMBO Molecular Medicine
    • Molecular Systems Biology
    • Rockefeller University Press
    • Journal of Cell Biology
    • Journal of Experimental Medicine
    • Journal of General Physiology
    • Cold Spring Harbor Laboratory Press
    • Genes & Development
    • Genome Research
  • My alerts
Life Science Alliance

Advanced Search

  • Home
  • Articles
    • Newest Articles
    • Current Issue
    • Methods & Resources
    • Archive
    • Subjects
  • Collections
  • Submit
    • Submit a Manuscript
    • Author Guidelines
    • License, Copyright, Fee
    • FAQ
    • Why Submit
  • About
    • About Us
    • Editors & Staff
    • Board Members
    • Licensing and Reuse
    • Reviewer Guidelines
    • Privacy Policy
    • Advertise
    • Contact Us
    • LSA LLC
  • Alerts
  • Follow lsa Template on Twitter
Research Article
Transparent Process
Open Access

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

Matilda R Jackson, Karagh E Loring, Claire C Homan, Monica HN Thai, Laura Määttänen, View ORCID ProfileMaria Arvio, Irma Jarvela, Marie Shaw, Alison Gardner, View ORCID ProfileJozef Gecz, View ORCID ProfileCheryl Shoubridge  Correspondence email
Matilda R Jackson
1Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karagh E Loring
1Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claire C Homan
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monica HN Thai
1Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Määttänen
3Department of Child Neurology, Turku University Hospital, Turku, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Arvio
3Department of Child Neurology, Turku University Hospital, Turku, Finland
4Joint Authority for Päijät-Häme Social and Health Care, Lahti, Finland
5PEDEGO, Oulu University Hospital, Oulu, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Maria Arvio
Irma Jarvela
6Department of Medical Genetics, University of Helsinki, Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marie Shaw
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alison Gardner
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jozef Gecz
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
7South Australian Health and Medical Research Institute, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jozef Gecz
Cheryl Shoubridge
1Intellectual Disability Research, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
2Department of Paediatrics, Robinson Research Institute, University of Adelaide, Adelaide, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Cheryl Shoubridge
  • For correspondence: Cheryl.shoubridge@adelaide.edu.au
Published 22 August 2019. DOI: 10.26508/lsa.201900386
  • Article
  • Figures & Data
  • Info
  • Metrics
  • Reviewer Comments
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Supplementary Materials
  • Figure S1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure S1. CRISPR/Cas9 targeting of Iqsec2 exon 3 designed to cause a frameshift and subsequent loss-of-function mutation.

    (A) Schematic of the exon–intron structure of Iqsec2 long (NM_001114664) and short (NM_001005475) isoforms, with the dashed box indicating consensus sequence. (B) Zoomed-in schematic of Iqsec2 exon 2–4 (exon 2 long = 2L and exon 2 short = 2S) with CRISPR guides (arrows) 63 bp upstream and 120 bp downstream of exon 3 (diagonal line fill), beginning at genomic position ChrX:152202845bp and ending at genomic position ChrX:152203,89bp (GRCm38/mm10) of the Iqsec2 positive strand, deleting exon 3 and 183 bp of the flanking intronic sequence, resulting in a predicted 445-bp deletion. (C) Complementary DNA region of exon 3 (uppercase in red) and flanking intronic sequence (lower case in black) showing the location of the CRISPR guides (blue) (5′-TCTAGTGTACTCACTCAGTT-3′ and 5′-AGGCTGGAACTGGCGAAAAC-3′) and PAM sites (orange) and the putative cut sites within the guides shown by “/” (blue). (D) Protein structure of Iqsec2 long (NP_001108136) and short (NP_001005475) isoforms, with white and black boxes depicting alternate exons, with dashed box indicating consensus sequence. CRISPR/Cas9 targeting of exon 3 (red diagonal line fill) results in a premature stop codon (red symbol) at c.159 (short isoform) and c.774 (long isoform) and subsequent truncation of the protein 13 amino acids from the new exon 2–4 boundary, with wild-type (black) and Iqsec2 KO (red) protein sequence presented for both isoforms. The PTC is 361 bp from the CRISPR/Cas9 generated exon–exon junction, predicted to result in mRNA degradation via the nonsense-mediated decay pathway and subsequent lack of a (truncated) protein.

  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1. CRISPR/Cas9 targeting of Iqsec2 resulted in absent (KO males) or reduced (KO HET females) Iqsec2/Iqsec2 expression.

    (A) Schematic of the exon–intron structure of Iqsec2 long (NM_001114664) and short (NM_001005475) isoforms, with the dashed box indicating consensus sequence. Zoomed-in schematic of Iqsec2 exon 2–4 (exon 2 long = 2L and exon 2 short = 2S) with CRISPR guides (arrows) flanking exon 3 (diagonal line fill), resulting in a predicted 445-bp deletion. Actual deletion size (highlighted by an orange box) shown flanking CRISPR guide putative cut sites in Founder A, with sex and total deletion size shown on left-hand side. (B) RT-PCR amplification of exon 2/3 boundary, exon 1 (short isoform), and exon 1 (long isoform) to exon 4 of 3 male founders, and subsequent progeny from founder A. (C) qPCR of three founder males (grouped) and subsequent progeny from founder A. Results are expressed as mean relative expression (±SEM; n = 3 founders, n = 6 Iqsec2 KO hemizygous males (KO), n = 6 Iqsec2 KO heterozygous females [HET]) normalised to wild types, which were pooled and averaged dependent on sex (n = 4 female wild type, n = 5 male wild type). (C) TaqMan gene expression assay probes spanning (i) exon 3–4 boundary, (ii) exon 11–12 boundary, and (iii) exon 13–14 boundary with gapdh used as a housekeeper. (D) Western blot analysis of Iqsec2 and Iqsec3 expression in three founder males and subsequent progeny from founder A. Blots were imported into Image Studio (Li-Cor Biosciences) and band intensities normalised to their respective beta-actin (Actb) loading control. Wild types were pooled and averaged dependent on sex (n = 2 female wild type, n = 2 male wild type). White spaces indicate a cropped image. # indicates significant difference between HET and founder, P < 0.0001 one-way ANOVA, Tukey’s HSD, ^ indicates significant difference between HET and KO, P < 0.0001; one-way ANOVA, Tukey’s HSD.

  • Figure S2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure S2. CRISPR/Cas9 gene editing generated four Iqsec2 KO founder mice with larger than expected deletions.

    (A) PCR amplification of intron 2–4 from genomic DNA from each founder, with a wild type shown for reference. (B) PCR amplification of neighbouring exons. Genomic DNA amplicons for exon 2 (both short and long isoform) and exon 5 are present in all four founder mice, and at the same size as their wild-type control. Amplification of exon 4 was unsuccessful in founder males B and C, suggesting that CRISPR/Cas9 deletion of exon 3 had also affected the neighbouring exon. White spaces indicate a cropped image; full images can be viewed online in Fig S3. (C) Zoomed-in schematic of Iqsec2 exon 2–4 (exon 2 long = 2L and exon 2 short = 2S). Sex and total deletion size for each founder presented on the left-hand side of the schematic. Actual deletion size (highlighted by an orange box) showing flanking CRISPR guide putative cut sites, with DNA sequence electropherograms and genomic coordinates of each breakpoint below (aligned to wild-type Iqsec2 NM_001114664; GRCm38/mm10), where orange lettering demonstrates disagreement with reference sequence. Identified breakpoint indicated by an arrow (↓), with reference sequence that could have been removed by either CRISPR guide depicted by red lettering above and a red line (–) below the electropherogram. Intronic sequence (lower case) and exonic sequence (upper case) are shown above the DNA electropherograms.

  • Figure S3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure S3. The loss of Iqsec2 is not compensated by elevated levels of Iqsec3 protein.

    The protein abundance of Iqsec3 measured in the postnatal cortex of wild-type and Iqsec2 KO animals: male (WT/Black; n = 8), hemizygous KO males (KO/blue; n = 6), female wild-type animals (WT/grey; n = 8), and heterozygous KO females (Het/pink; n = 11). Different postnatal ages indicated; 60–80 d (square), 120–180 d (circle), and >200 d (triangle) of age. Mean (±SEM) data presented, with no significant differences between any groups when analysed by one-way ANOVA.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2. Iqsec2 KO hemizygous males and heterozygous females exhibit spontaneous seizures and reduced survival, which was not observed in their wild-type control littermates.

    The total number of animals phenotyped include KO; n = 46 (blue) and HET; n = 153 (pink). (A, B, C, D, E) Percentage seizure occurrence and (B) survival presented at daily intervals from birth, with both further subclassified as (C) age at observed first seizure, (D) age at unexpected death, and (E) occurrence of repeat seizures presented as median (±min/max), where each dot represents an individual animal. Unexpected death was classified as humane euthanasia or found dead presumed because of seizure or status epilepticus and does not include those individuals taken for experimental end point. These data do not include any movement phenotypes observed. (F) Iqsec2 heterozygous females (Het/pink; n = 13) have reduced levels of Iqsec2 protein compared with female wild-type animals (WT/grey; n = 11). Mean (±SEM) data presented. The animals with observed seizures are denoted as stars. There were no significant differences in Iqsec2 protein abundance between male (WT/Black; n = 10) and female wild-type animals (WT/grey; n = 11). * indicates significant difference between KO males and HET females, P < 0.05, two-tailed, unpaired t test, # indicates P < 0.0001, two-tailed, paired t test, ^ indicates P < 0.05 between HET/KO and female WT controls, two-tailed, unpaired t test.

  • Figure S4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure S4. Iqsec2 KO heterozygous females have reduced breeding success.

    Pregnancy outcomes and subsequent nurturing of live litters generated for first (n = 24) litters of Iqsec2 KO heterozygous females show as many as 37% of females were unable to produce live young either because of being unable to fall pregnant (or retain their pregnancy because of reabsorption) (grey) or were found dead (red) presumed because of seizure or status epilepticus, as this was not observed in wild-type female breeders. Of the breeders able to produce live young (blue), only 20% produced a milk supply and fed their young (green), whereas most females either never fed their young at all (orange) or only fed/nurtured their young for a maximum of 1 day (pale orange). This phenomenon was observed not only with first-time mothers but also in subsequent litters. Feeding/nurturing success was not obviously correlated with observed seizure occurrence. Breeding females were set up between 3 and 4 mo of age with wild-type C57/Bl6 stud males, with males remaining with their respective female for the duration of breeding. A minimum of 2 mo was given to produce a live litter.

  • Figure S5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure S5. Iqsec2 KO heterozygous female mice demonstrate altered anxiety, increased locomotor activity, and reduced spatial learning and memory.

    (A, B) Behavioural tests undertaken at monthly intervals between 1 and 6 mo of age show that Iqsec2 KO heterozygous females (HET/pink) (n = 4 at 1 mo; n = 8 at 2–3 mo, n = 7 at 4–6 mo) compared with their wild-type female controls (WT/grey) (n = 3 at 1 mo; n = 6 at 2–6 mo) showed (A) reduced neuromuscular strength on the inverted grid and (B) decreased fear response in the elevated zero maze compared with their wild-type female controls (WT/grey; n = 3–6). Mean (±SEM) data presented.

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3. Iqsec2 KO heterozygous females display altered anxiety, increased locomotor activity and reduced spatial learning and memory.

    (A, B, C, D, E, F, G) Behavioural tests undertaken at monthly intervals between 1 and 6 mo of age show that Iqsec2 KO heterozygous females (HET/pink) (n = 4 at 1 mo; n = 8 at 2–3 mo, n = 7 at 4–6 mo) compared with their wild-type female controls (WT/grey) (n = 3 at 1 mo; n = 6 at 2–6 mo) demonstrate (A) increased speed across multiple apparatus (sociability apparatus shown), (B) increased exploratory behaviour in the open field test, (C) increased anxiety in open field test, (D) decreased fear response in the elevated zero maze, (E) reduced total interaction time in the sociability apparatus regardless of familiar or novel cage occupant, (F) decreased novel recognition in the Y-maze, (G) and reduced spatial learning in the Barnes maze (conducted at 6 mo of age). Mean (±SEM) data presented, where * indicates significance between HET/KO and WT controls, # indicates significant between HET time points, two-way ANOVA with Tukey’s HSD.

  • Figure 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 4. Neuroanatomy changes in Iqsec2 KO mouse brains.

    (A, B) Nissl staining of brain sections in both (A) coronal and (B) sagittal orientations from adult wild-type and heterozygous KO females demonstrate there is no gross disturbance to brain morphology. Scale bars shown for each set of pictomicrographs. (C) The thickness of the corpus callosum (CC) measured where the (1) start and (2) end of the cingulum intercepts the CC in three coronal sections for each of n = 4 animals per genotype is significantly thinner in heterozygous female (HET/pink) mice compared with wild-type female (WT/Grey) mice. (D) Heterozygous females have increased total hippocampal and dentate gyrus volume compared with wild-type littermates (n = 4 each). (E) The area of the brain was measured in animals from 60 to 155 d postnatal age in sagittal sections in HET/pink and WT/grey females (a total 36 sections measured per genotype: nine sections each for n = 4 animals). The Iqsec2 HetKO animals with observed seizures are denoted by stars. Mean (±SEM) data presented where # indicates P < 0.001, and # # indicates P < 0.0001, two-tailed, unpaired t test between wild-type and heterozygous females.

  • Figure 5.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 5. Embryonic (E)17.5 cultured cortical neurons from Iqsec2 heterozygous females (HET/pink; n = 449 electrodes from n = 12 embryos) exhibit hallmarks of immature synaptic networks when compared with their respective wild-type (WT) control littermates (WT female/grey n = 256 electrodes from n = 7 embryos).

    (A, B, C, D) Representative raster plots for (A.i) WT female and (A.ii) HET female after 21 d in culture. Quantitatively, HET cultures showed an increased (B) spike count, (C) burst count, and (D) mean burst duration compared with wild-type control littermates. Mean (±SEM) data presented, where * indicates significance between HET and WT control, two-tailed, unpaired t test , where P < 0.05.

  • Figure 6.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 6. The levels of activated Arf6 in cortical tissue are elevated because of Iqsec2 KO.

    (A) Biochemical assays to measure the levels of activated Arf6 (G-LISA) undertaken in cortical tissues of animals across postnatal development between 2 and 9 mo of age show that (A) the levels of activated Arf6 in wild-type male mice (WT/black) (n = 4) are elevated in age-matched wild-type female mice (WT/grey) (n = 5). (B) Iqsec2 KO hemizygous males (KO/blue, n = 6) and heterozygous KO females (Het/pink; n = 9) both display increased levels of activated Arf6 compared with the sex-matched wild-type controls listed above. (C) The abundance of Arf6 protein measured by immunoblot was not significantly different between any genotype groups. The Iqsec2 KO animals with observed seizures are denoted by stars. Mean (±SEM) data presented, where * indicates significance between WT female control and HET/KO, P < 0.05, 2-tailed, unpaired t test.

  • Figure 7.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 7. Identification of a c.556C > A (NM_001111125.2) variant resulting in a premature stop codon at p.(S189*) (NP_001104595) in IQSEC2.

    (A) Pedigree of family. Open symbols represent unaffected individuals and filled black circle represents female with profound-to-severe intellectual disability and epilepsy. Normal (N) and mutant (M) alleles shown for proband. (B) Asymmetrical facial features, prominent angle of the jaw and low-set, large ears of II-2 (front and side). (C) DNA sequence electropherograms for the chrX:g.53349756 (GRCh37/hg19 assembly); c.556C>A mutation in exon 1 of 15 of IQSEC2 in II-2 affected female. (D) Predicted impact of novel variant in IQSEC2. The exon–intron structure of the longest isoform of the IQSEC2 gene (NM_001111125.2) with 15 exons, the ATG and open reading frame and stop codon position in black and 5′ and -3′ untranslated regions in light grey. The predicted protein structures (NP_001104595) with known functional domains highlighted; coiled–coiled (CC-red), IQ-like (orange) Sec7 enzyme domain (Green), PH domain (purple), and PDZ-binding motif (Blue), corresponding amino acids listed below each domain. The variant c.566C>A replaces the codon for Serine (p.189) for a stop codon and is predicted to result in nonsense-mediated mRNA decay and loss of the protein from the mutant allele.

Tables

  • Figures
  • Supplementary Materials
    • View popup
    Table 1.

    Pathogenic loss-of-function variants in IQSEC2 in females with intellectual disability and other comorbidities.

    cDNAExProteinDomFamilyDD/IDSeizuresBehavioural/Psychiatric/Physical featuresRef
    c.55_151delinsAT1p.Ala19Ilefs*32—P1Mild IDNoneSpeech deficits—pronunciation, syntax issues at 6.5 years. Tantrums, anxiety(29)
    c.83_85del1p.Asp28delCC108286Rett likeNoneLoss of language. Regression stabilization, gait abnormalities(30)
    c.273_282del1p.Asp91Lysfs*112—P7Rett likeRegression stabilization, gait abnormalities, stereotypic hand movements, inappropriate laughing/screaming spells. Partial or loss of spoken language.(31)
    c.566C>A1p.(S189*)—Fin2Severe-profound IDGeneralised seizures (18 mo)Limited speech, low-set large ears, asymmetric facial features, mild hypertrichosis, mild ASD.This report
    c.804delC3p.Tyr269Thrfs*3—48SeizuresLimited phenotype reported.(32)
    c.854del3p.Pro285Leufs*21—P11Severe IDSeizures (12 mo) tonic–clonicSays words at 16 years. Limb rigidity, walking instability.(29)
    c.928G>T3p.Glu310*—P16Mild-mod DDFENo ASD or other features. Nonverbal at 3 years.(33)
    c.1556_1599delACCT5p.Tyr519Trpfs*87—P10DD, Severe to profound IDNoneHypotonia, first word at 2 years, stereotypies, and dysmorphic features.(34)
    c.1591C>T5p.Arg531*—P3DD, Severe to profound IDTonic–clonic, absenceAutism, first words at 11 mo, hypotonia, stereotypies, ataxic gait(34)
    c.1744_1763del5p.Arg582Cysfs*9—P16Mild DDFocal epilepsy (17 mo)50–60 words at 3 years. Autistic behaviour, hypertonia.(29)
    c.1983_1999del5p.Leu662Glnfs*25—P17Global DDFocal epilepsy (11 mo)Babbling at 16 mo Hypertonia.(29)
    c.2052_2053delCG5p.Cys684*—47SeizuresLimited phenotype reported.(32)
    c.2078delG5p.Gly693Valfs*29P18Mod global DDNoneNonverbal at 2.8 years. Self-injurious behaviour, hypotonia(29)
    c.2203C>T5p.Gln735*—T17563Mild IDSGE (5 years)—regression with nonconvulsive SE. Absence to tonic–clonic and myoclonic seizures, drop attacks. Offset at 38 years.(35)
    c.2272C>T5p.Arg758*—P19Severe IDMultifocal epilepsy (23 mo)3 words at 11.3 years. Self-injurious behaviours.(29)
    P20Mod IDSeizures (9 years 4 mo) GTCS, focal, atypical absencesSpeaks sentences, reasoning difficulties
    c.2317C>T6p.Gln773*Sec7P6Global DDSeizures (18 mo)Hypotonic, strabismus, dysmorphic face(36)
    P23Mod IDSeizures (14 years), GTCS, absencesFew words at 43 years. ASD (13 years) aggressive.(29)
    c.2317_2332del6p.Gln773Glyfs*25Sec7P24Seizures (6 years)Sentences at 11.3 years(29)
    c.2679_2680insA8p.Asp894fs*10Sec7K2DD, Mod-severe IDEpilepsy4 affected sisters, nonverbal (2), language delay (1), aggressive when young and ASD traits (2)(37)
    c.2776C>T9p.Arg926*Sec7P3Severe ID Rett likeEEASD (balance & hand stereotypies), pain sensitivity & aggressive. Speech delay, regression at 2 years. Now nonverbal(38)
    P26Profound IDLGS (23 mo)Nonverbal at 11.3 years. Autistic behaviour, truncal hypotonia, strabismus.(29)
    9p.Tyr933*Sec7M2189Global DD Mod IDASD, sleep disturbances, behavioural aspects, oral motor dyspraxia, strabismus. Marked speech delay, nonverbal at 14 years.(39)
    c.2854C>T9p.Gln952*PHP27Severe IDEE (12 years), absences, GTCSNonverbal at 16 years. Autistic behaviour, dystonia, tremor, ataxia.(29)
    c.2911C>T10p.Arg971*PHP8DD, Severe to profound IDSeizuresNo ASD. Stereotypies and dysmorphic features.(34)
    P11DD, Severe to profound IDSeizuresAutism, first word at 2.3–3 years, stereotypies and dysmorphic features, ataxic gait(34)
    c.3079delC11p.Leu1027Serfs*75PHP29Mod-severe IDNone10 words at 8 years(29)
    c.3163C>T12p.Arg1055*PHPat19Severe IDEpilepsyBorderline macrocephaly, skewed X-inactivation (97:3)(40)
    P31Mod-severe IDSeizures (5 years 8 mo) GTCS, focal dyscognitive3 word sentences, and 20 words at 8 years. Autistic behaviour, Global hypotonia, aggression, hyperactivity.(29)
    c.3278C>A13p.Ser1093*—P36Severe IDNoneFew words, rare sentences at 13 years.(29)
    c.3322C>T13p.Gln1108*—KOEE(41)
    c.3433C>T13p.Arg1145*—P39Severe IDFocal epilepsy (11 mo) focal, tonic, tonic–clonicNonverbal at 11 years. Autistic behaviour.(29)
    c.3457del14p.Arg1153Glyfs*244—P40Severe IDIS (7 mo) spasms, focal, absence, tonic, myoclonic jerksNonverbal at 20 years. Autistic behaviour, truncal hypotonia. MRI mild atrophy and cerebral white matter hyperintensities.(29)
    c.4039dupG15p.Ala1347Glyfs*40—1098 MEE (19 mo)ASD, macrocephaly(42)
    P41Mild-mod IDSeizures (3 years) absence and fallsSpeaks sentences, writes first name, counts to 15 at 11 years. Mild autistic behaviour.(29)
    c.4401del15p.Gly1468Alafs*27—P42Mod-severe IDNoneShort sentences at 11 years. Attention deficit/hyperactivity(29)
    c.4419_4420insC15p.Ser1474Glnfs*—P6DD, Severe to profound IDAbsence, complexAutism, hypotonia. First words at 7 years. Ataxic gait, stereotypies, bouts of laughter, self-injurious behaviour.(34)
    Twin sister of P6P7DD, Mild IDNoAutism, first words 11.5 mo. Ataxic gait
    • ASD, autistic spectrum disorder; DD, developmental delay; EE, epileptic encephalopathy; GTCS, generalised tonic–clonic seizures; IS, infantile spasms; SGE, symptomatic generalised epilepsy.

    • Del, deletion; dup, duplication. Numbers (alone) in brackets indicate number of affected individuals.

    • Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence for IQSEC2 (GenBank: NM_001111125.2).

    • View popup
    Table 2.

    Correlation of behavioural findings in Iqsec2 KO mice and patients with loss-of-function mutations.

    TestMeasureFindingPatient trait
    Inverted GridNeuromuscular strengthReducedDystonia/stereotypic hand movements
    Open FieldExplorationIncreasedHyperactivity and psychiatric issues
    Anxiety (open spaces)Increased
    Elevated zero mazeFear response (height)ReducedPsychiatric issues
    Y-mazeShort term memoryReducedIntellectual disability
    SociabilitySocial traitsReducedAutistic-like features
    Barnes MazeCognitionReducedIntellectual disability

Supplementary Materials

  • Figures
  • Tables
  • Table S1 Primer sets for genotyping and exon amplification.

  • Table S2 Off-target analysis using two computational tools.

  • Video 1

    Shows involuntary, uncontrolled, unilateral head movements.Download video

  • Video 2

    Shows repetitive forelimb clonus.Download video

  • Video 3

    Shows uncontrolled convulsions with bilateral forelimb outward stretching.Download video

  • Video 4

    Shows full body tonic–clonic seizures with loss of postural control.Download video

  • Supplemental Data 1.

    Patient phenotype.[LSA-2019-00386_Supplemental_Data_1.docx]

PreviousNext
Back to top
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Life Science Alliance.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females
(Your Name) has sent you a message from Life Science Alliance
(Your Name) thought you would like to see the Life Science Alliance web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Heterozygous loss of function of IQSEC2
Matilda R Jackson, Karagh E Loring, Claire C Homan, Monica HN Thai, Laura Määttänen, Maria Arvio, Irma Jarvela, Marie Shaw, Alison Gardner, Jozef Gecz, Cheryl Shoubridge
Life Science Alliance Aug 2019, 2 (4) e201900386; DOI: 10.26508/lsa.201900386

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Heterozygous loss of function of IQSEC2
Matilda R Jackson, Karagh E Loring, Claire C Homan, Monica HN Thai, Laura Määttänen, Maria Arvio, Irma Jarvela, Marie Shaw, Alison Gardner, Jozef Gecz, Cheryl Shoubridge
Life Science Alliance Aug 2019, 2 (4) e201900386; DOI: 10.26508/lsa.201900386
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
Issue Cover

In this Issue

Volume 2, No. 4
August 2019
  • Table of Contents
  • Cover (PDF)
  • About the Cover
  • Masthead (PDF)
Advertisement

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgements
    • References
  • Figures & Data
  • Info
  • Metrics
  • Reviewer Comments
  • PDF

Subjects

  • Genetics, Gene Therapy & Genetic Disease

Related Articles

  • No related articles found.

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Aporrectodea caliginosa adaption and acclimatisation
  • Telescoping bimodal latent Dirichlet allocation
  • Neutrophils delay repair in Wallerian degeneration
Show more Research Article

Similar Articles

EMBO Press LogoRockefeller University Press LogoCold Spring Harbor Logo

Content

  • Home
  • Newest Articles
  • Current Issue
  • Archive
  • Subject Collections

For Authors

  • Submit a Manuscript
  • Author Guidelines
  • License, copyright, Fee

Other Services

  • Alerts
  • Twitter
  • RSS Feeds

More Information

  • Editors & Staff
  • Reviewer Guidelines
  • Feedback
  • Licensing and Reuse
  • Privacy Policy

ISSN: 2575-1077
© 2022 Life Science Alliance LLC

Life Science Alliance is registered as a trademark in the U.S. Patent and Trade Mark Office and in the European Union Intellectual Property Office.