Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features

Muhammad Ansar, Farid Ullah, Sohail A. Paracha, Darius J. Adams, Abbe Lai, Lynn Pais, Justyna Iwaszkiewicz, Francisca Millan, Muhammad T. Sarwar, Zehra Agha, Sayyed Fahim Shah, Azhar Ali Qaisar, Emilie Falconnet, Vincent Zoete, Emmanuelle Ranza, Periklis Makrythanasis, Federico A. Santoni, Jawad Ahmed, Nicholas Katsanis, Christopher WalshErica E. Davis, Stylianos E. Antonarakis

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.

Original languageEnglish (US)
Pages (from-to)1073-1087
Number of pages15
JournalAmerican Journal of Human Genetics
Volume104
Issue number6
DOIs
StatePublished - Jun 6 2019
Externally publishedYes

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Cytoplasmic Dyneins
Microcephaly
Intellectual Disability
Zebrafish
Clustered Regularly Interspaced Short Palindromic Repeats
Exome
Dyneins
RNA Splice Sites
Corpus Callosum
Nucleic Acid Databases
Neurogenesis
Pedigree
Mitosis
Genes
Larva
Cell Cycle
Homeostasis
Cell Death
Head
Apoptosis

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Ansar, Muhammad ; Ullah, Farid ; Paracha, Sohail A. ; Adams, Darius J. ; Lai, Abbe ; Pais, Lynn ; Iwaszkiewicz, Justyna ; Millan, Francisca ; Sarwar, Muhammad T. ; Agha, Zehra ; Shah, Sayyed Fahim ; Qaisar, Azhar Ali ; Falconnet, Emilie ; Zoete, Vincent ; Ranza, Emmanuelle ; Makrythanasis, Periklis ; Santoni, Federico A. ; Ahmed, Jawad ; Katsanis, Nicholas ; Walsh, Christopher ; Davis, Erica E. ; Antonarakis, Stylianos E. / Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 6. pp. 1073-1087.
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abstract = "Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.",
author = "Muhammad Ansar and Farid Ullah and Paracha, {Sohail A.} and Adams, {Darius J.} and Abbe Lai and Lynn Pais and Justyna Iwaszkiewicz and Francisca Millan and Sarwar, {Muhammad T.} and Zehra Agha and Shah, {Sayyed Fahim} and Qaisar, {Azhar Ali} and Emilie Falconnet and Vincent Zoete and Emmanuelle Ranza and Periklis Makrythanasis and Santoni, {Federico A.} and Jawad Ahmed and Nicholas Katsanis and Christopher Walsh and Davis, {Erica E.} and Antonarakis, {Stylianos E.}",
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Ansar, M, Ullah, F, Paracha, SA, Adams, DJ, Lai, A, Pais, L, Iwaszkiewicz, J, Millan, F, Sarwar, MT, Agha, Z, Shah, SF, Qaisar, AA, Falconnet, E, Zoete, V, Ranza, E, Makrythanasis, P, Santoni, FA, Ahmed, J, Katsanis, N, Walsh, C, Davis, EE & Antonarakis, SE 2019, 'Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features', American Journal of Human Genetics, vol. 104, no. 6, pp. 1073-1087. https://doi.org/10.1016/j.ajhg.2019.04.002

Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features. / Ansar, Muhammad; Ullah, Farid; Paracha, Sohail A.; Adams, Darius J.; Lai, Abbe; Pais, Lynn; Iwaszkiewicz, Justyna; Millan, Francisca; Sarwar, Muhammad T.; Agha, Zehra; Shah, Sayyed Fahim; Qaisar, Azhar Ali; Falconnet, Emilie; Zoete, Vincent; Ranza, Emmanuelle; Makrythanasis, Periklis; Santoni, Federico A.; Ahmed, Jawad; Katsanis, Nicholas; Walsh, Christopher; Davis, Erica E.; Antonarakis, Stylianos E.

In: American Journal of Human Genetics, Vol. 104, No. 6, 06.06.2019, p. 1073-1087.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features

AU - Ansar, Muhammad

AU - Ullah, Farid

AU - Paracha, Sohail A.

AU - Adams, Darius J.

AU - Lai, Abbe

AU - Pais, Lynn

AU - Iwaszkiewicz, Justyna

AU - Millan, Francisca

AU - Sarwar, Muhammad T.

AU - Agha, Zehra

AU - Shah, Sayyed Fahim

AU - Qaisar, Azhar Ali

AU - Falconnet, Emilie

AU - Zoete, Vincent

AU - Ranza, Emmanuelle

AU - Makrythanasis, Periklis

AU - Santoni, Federico A.

AU - Ahmed, Jawad

AU - Katsanis, Nicholas

AU - Walsh, Christopher

AU - Davis, Erica E.

AU - Antonarakis, Stylianos E.

PY - 2019/6/6

Y1 - 2019/6/6

N2 - Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.

AB - Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.

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