INPP4A-related genetic and phenotypic spectrum and functional relevance of subcellular targeting of INPP4A isoforms.

IF 1.6 4区 医学 Q3 CLINICAL NEUROLOGY
Laura Hecher, Frederike L Harms, Jasmin Lisfeld, Malik Alawi, Jonas Denecke, Kerstin Kutsche
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引用次数: 0

Abstract

Type I inositol polyphosphate-4-phosphatase (INPP4A) belongs to the group of phosphoinositide phosphatases controlling proliferation, apoptosis, and endosome function by hydrolyzing phosphatidylinositol 3,4-bisphosphate. INPP4A produces multiple transcripts encoding shorter and longer INPP4A isoforms with hydrophilic or hydrophobic C-terminus. Biallelic INPP4A truncating variants cause a spectrum of neurodevelopmental disorders ranging from moderate intellectual disability to postnatal microcephaly with developmental and epileptic encephalopathy and (ponto)cerebellar hypoplasia. We report a girl with the novel homozygous INPP4A variant NM_001134224.2:c.2840del/p.(Gly947Glufs*12) (isoform d). She presented with postnatal microcephaly, global developmental delay, visual impairment, myoclonic seizures, and pontocerebellar hypoplasia and died at the age of 27 months. The level of mutant INPP4A mRNAs in proband-derived leukocytes was comparable to controls suggesting production of C-terminally altered INPP4A isoforms. We transiently expressed eGFP-tagged INPP4A isoform a (NM_004027.3) wildtype and p.(Gly908Glufs*12) mutant [p.(Gly947Glufs*12) according to NM_001134224.2] as well as INPP4A isoform b (NM_001566.2) wildtype and p.(Asp915Alafs*2) mutant, previously reported in family members with moderate intellectual disability, in HeLa cells and determined their subcellular distributions. While INPP4A isoform a was preferentially found in perinuclear clusters co-localizing with the GTPase Rab5, isoform b showed a net-like distribution, possibly localizing near and/or on microtubules. Quantification of intracellular localization patterns of the two INPP4A mutants revealed significant differences compared with the respective wildtype and similarity with each other. Our data suggests an important non-redundant function of INPP4A isoforms with hydrophobic or hydrophilic C-terminus in the brain.

Abstract Image

INPP4A相关的遗传和表型谱以及亚细胞靶向INPP4A亚型的功能相关性
I型肌醇多磷酸-4-磷酸酶(INPP4A)是一类通过水解磷脂酰肌醇3,4-二磷酸来控制增殖、凋亡和核内体功能的磷酸肌醇磷酸酶。INPP4A产生多个转录本,编码具有亲水性或疏水性c端的较短和较长的INPP4A同工型。双等位基因INPP4A截断变异引起一系列神经发育障碍,从中度智力残疾到产后小头畸形伴发育性和癫痫性脑病以及(ponto)小脑发育不全。我们报告了一名患有新型纯合子INPP4A变异NM_001134224.2:c.2840del/p.(Gly947Glufs*12) (d型异构体)的女孩,她表现为出生后小头畸形、整体发育迟缓、视力障碍、肌阵挛性癫痫和桥小脑发育不全,并于27个月时死亡。先证衍生的白细胞中突变INPP4A mrna的水平与对照组相当,这表明产生了c端改变的INPP4A亚型。我们在HeLa细胞中瞬时表达了egfp标记的INPP4A亚型a (NM_004027.3)野生型和p.(Gly908Glufs*12)突变体[根据NM_001134224.2],以及先前在中度智力残疾家庭成员中报道的INPP4A亚型b (NM_001566.2)野生型和p.(Asp915Alafs*2)突变体,并确定了它们的亚细胞分布。INPP4A异构体a优先存在于与GTPase Rab5共定位的核周围簇中,而异构体b则呈现网状分布,可能定位于微管附近或微管上。对两个INPP4A突变体的细胞内定位模式进行定量分析,发现与各自的野生型相比存在显著差异,且具有相似性。我们的数据表明,在大脑中具有疏水或亲水性c端的INPP4A亚型具有重要的非冗余功能。
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来源期刊
Neurogenetics
Neurogenetics 医学-临床神经学
CiteScore
3.90
自引率
0.00%
发文量
24
审稿时长
6 months
期刊介绍: Neurogenetics publishes findings that contribute to a better understanding of the genetic basis of normal and abnormal function of the nervous system. Neurogenetic disorders are the main focus of the journal. Neurogenetics therefore includes findings in humans and other organisms that help understand neurological disease mechanisms and publishes papers from many different fields such as biophysics, cell biology, human genetics, neuroanatomy, neurochemistry, neurology, neuropathology, neurosurgery and psychiatry. All papers submitted to Neurogenetics should be of sufficient immediate importance to justify urgent publication. They should present new scientific results. Data merely confirming previously published findings are not acceptable.
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