정형록 (Hyung-Lok Chung) Baylor College of Medicine
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Am. J. Hum. Genet., Available online 10 October 2019 | https://doi.org/10.1016/j.ajhg.2019.09.013
Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature
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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.

Keywords : autosomal recessive; Drosophila; schizo, mice; BRAG2; axon guidance; dendritic spines

Category: Genetics, Neuroscience, Developmental_Biology
추천자 : 목정완 (KAIST)
인지기능, 발달 등에 영향을 주는 미진단 질환의 유전적 원인과 작용 기작을 환자의 염기서열 정보를 이용하여 밝혀냄. 초파리와 쥐 모델 등을 활용하여 밝혀낸 이 결과는 환자의 DNA 정보를 기반으로 검증되었기 때문에 임상적 가치와 효용이 클 것으로 생각됨. 또한 상대적으로 연구에서 소외된 미진단 질환 환자들을 위한 연구가 진행되었다는 점에서 과학 기술의 보편적 평등적 가치에 기여하였다고 판단되어 이 논문을 추천함.
등록일 2019.10.23
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