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Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature

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Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. / Ansar, Muhammad; Chung, Hyung-Lok; Al-Otaibi, Ali; Elagabani, Mohammad Nael; Ravenscroft, Thomas A; Paracha, Sohail A; Scholz, Ralf; Abdel Magid, Tayseer; Sarwar, Muhammad T; Shah, Sayyed Fahim; Qaisar, Azhar Ali; Makrythanasis, Periklis; Marcogliese, Paul C; Kamsteeg, Erik-Jan; Falconnet, Emilie; Ranza, Emmanuelle; Santoni, Federico A; Aldhalaan, Hesham; Al-Asmari, Ali; Faqeih, Eissa Ali; Ahmed, Jawad; Kornau, Hans-Christian; Bellen, Hugo J; Antonarakis, Stylianos E.

In: AM J HUM GENET, Vol. 105, No. 5, 07.11.2019, p. 907-920.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ansar, M, Chung, H-L, Al-Otaibi, A, Elagabani, MN, Ravenscroft, TA, Paracha, SA, Scholz, R, Abdel Magid, T, Sarwar, MT, Shah, SF, Qaisar, AA, Makrythanasis, P, Marcogliese, PC, Kamsteeg, E-J, Falconnet, E, Ranza, E, Santoni, FA, Aldhalaan, H, Al-Asmari, A, Faqeih, EA, Ahmed, J, Kornau, H-C, Bellen, HJ & Antonarakis, SE 2019, 'Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature', AM J HUM GENET, vol. 105, no. 5, pp. 907-920. https://doi.org/10.1016/j.ajhg.2019.09.013

APA

Ansar, M., Chung, H-L., Al-Otaibi, A., Elagabani, M. N., Ravenscroft, T. A., Paracha, S. A., Scholz, R., Abdel Magid, T., Sarwar, M. T., Shah, S. F., Qaisar, A. A., Makrythanasis, P., Marcogliese, P. C., Kamsteeg, E-J., Falconnet, E., Ranza, E., Santoni, F. A., Aldhalaan, H., Al-Asmari, A., ... Antonarakis, S. E. (2019). Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. AM J HUM GENET, 105(5), 907-920. https://doi.org/10.1016/j.ajhg.2019.09.013

Vancouver

Ansar M, Chung H-L, Al-Otaibi A, Elagabani MN, Ravenscroft TA, Paracha SA et al. Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. AM J HUM GENET. 2019 Nov 7;105(5):907-920. https://doi.org/10.1016/j.ajhg.2019.09.013

Bibtex

@article{2cc2fe82cd1044d695a24ae2e932e1b1,
title = "Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature",
abstract = "We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.",
author = "Muhammad Ansar and Hyung-Lok Chung and Ali Al-Otaibi and Elagabani, {Mohammad Nael} and Ravenscroft, {Thomas A} and Paracha, {Sohail A} and Ralf Scholz and {Abdel Magid}, Tayseer and Sarwar, {Muhammad T} and Shah, {Sayyed Fahim} and Qaisar, {Azhar Ali} and Periklis Makrythanasis and Marcogliese, {Paul C} and Erik-Jan Kamsteeg and Emilie Falconnet and Emmanuelle Ranza and Santoni, {Federico A} and Hesham Aldhalaan and Ali Al-Asmari and Faqeih, {Eissa Ali} and Jawad Ahmed and Hans-Christian Kornau and Bellen, {Hugo J} and Antonarakis, {Stylianos E}",
note = "Copyright {\textcopyright} 2019. Published by Elsevier Inc.",
year = "2019",
month = nov,
day = "7",
doi = "10.1016/j.ajhg.2019.09.013",
language = "English",
volume = "105",
pages = "907--920",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature

AU - Ansar, Muhammad

AU - Chung, Hyung-Lok

AU - Al-Otaibi, Ali

AU - Elagabani, Mohammad Nael

AU - Ravenscroft, Thomas A

AU - Paracha, Sohail A

AU - Scholz, Ralf

AU - Abdel Magid, Tayseer

AU - Sarwar, Muhammad T

AU - Shah, Sayyed Fahim

AU - Qaisar, Azhar Ali

AU - Makrythanasis, Periklis

AU - Marcogliese, Paul C

AU - Kamsteeg, Erik-Jan

AU - Falconnet, Emilie

AU - Ranza, Emmanuelle

AU - Santoni, Federico A

AU - Aldhalaan, Hesham

AU - Al-Asmari, Ali

AU - Faqeih, Eissa Ali

AU - Ahmed, Jawad

AU - Kornau, Hans-Christian

AU - Bellen, Hugo J

AU - Antonarakis, Stylianos E

N1 - Copyright © 2019. Published by Elsevier Inc.

PY - 2019/11/7

Y1 - 2019/11/7

N2 - We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.

AB - We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.

U2 - 10.1016/j.ajhg.2019.09.013

DO - 10.1016/j.ajhg.2019.09.013

M3 - SCORING: Journal article

C2 - 31607425

VL - 105

SP - 907

EP - 920

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 5

ER -