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Biallelic variants in KIF14 cause intellectual disability with microcephaly.

ABSTRACT: Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

SUBMITTER: Makrythanasis P

PROVIDER: S-EPMC5839044 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Makrythanasis Periklis P Maroofian Reza R Stray-Pedersen Asbjørg A Musaev Damir D Zaki Maha S MS Mahmoud Iman G IG Selim Laila L Elbadawy Amera A Jhangiani Shalini N SN Coban Akdemir Zeynep H ZH Gambin Tomasz T Sorte Hanne S HS Heiberg Arvid A McEvoy-Venneri Jennifer J James Kiely N KN Stanley Valentina V Belandres Denice D Guipponi Michel M Santoni Federico A FA Ahangari Najmeh N Tara Fatemeh F Doosti Mohammad M Iwaszkiewicz Justyna J Zoete Vincent V Backe Paul Hoff PH Hamamy Hanan H Gleeson Joseph G JG Lupski James R JR Karimiani Ehsan Ghayoor EG Antonarakis Stylianos E SE

European journal of human genetics : EJHG 20180117 3

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and tw ...[more]

PMID: 29343805

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Project description:BackgroundCoat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as "coatopathies".MethodsWhole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (?-COP). To investigate Family 1's splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2's missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2's mutation.ResultsWe present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between ?-COP and ?'-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant ?-COP, with the mutant protein being retarded in the Golgi.ConclusionsThis adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

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Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Publications

Biallelic variants in KIF14 cause intellectual disability with microcephaly.

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