Journal of Human Genetics最新文献_第10页

A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms 与智力障碍、小头畸形和白内障有关的 RGS6 剪接受体变异会不成比例地促进 RGS6 同工酶亚型的表达。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-02-09 DOI: 10.1038/s10038-024-01220-1

K. E. Ahlers-Dannen, J. Yang, M. M. Spicer, D. Fu, A. DeVore, R. A. Fisher

{"title":"A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms","authors":"K. E. Ahlers-Dannen, J. Yang, M. M. Spicer, D. Fu, A. DeVore, R. A. Fisher","doi":"10.1038/s10038-024-01220-1","DOIUrl":"10.1038/s10038-024-01220-1","url":null,"abstract":"Intellectual disability (ID) is associated with an increased risk of developing psychiatric disorders, suggesting a common underlying genetic factor. Importantly, altered signaling and/or expression of regulator of G protein signaling 6 (RGS6) is associated with ID and numerous psychiatric disorders. RGS6 is highly conserved and undergoes complex alternative mRNA splicing producing ~36 protein isoforms with high sequence similarity historically necessitating a global approach in functional studies. However, our recent analysis in mice revealed RGS6 is most highly expressed in CNS with RGS6L(+GGL) isoforms predominating. A previously reported genetic variant in intron 17 of RGS6 (c.1369-1G>C), associated with ID, may provide further clues into RGS6L(+GGL) isoform functional delineation. This variant was predicted to alter a highly conserved canonical 3’ acceptor site creating an alternative branch point within exon 18 (included in a subset of RGS6L(+GGL) transcripts) and a frameshift forming an early stop codon. We previously identified this alternative splice site and demonstrated its use generates RGS6Lζ(+GGL) isoforms. Here, we show that the c.1369-1G>C variant disrupts the canonical, preferred (>90%) intron 17 splice site and leads to the exclusive use of the alternate exon 18 splice site, inducing disproportionate expression of a subset of isoforms, particularly RGS6Lζ(+GGL). Furthermore, RGS6 global knockout mice do not exhibit ID. Thus, ID caused by the c.1369-1G>C variant likely results from altered RGS6 isoform expression, rather than RGS6 isoform loss. In summary, these studies highlight the importance of proper RGS6 splicing and identify a previously unrecognized role of G protein signaling in ID.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"145-152"},"PeriodicalIF":3.5,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes ZFP36L2 在非综合征口面裂亚型中的遗传关联和功能验证。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-02-06 DOI: 10.1038/s10038-024-01222-z

Jialin Sun, Mujia Li, Huaqin Sun, Ziyuan Lin, Bing Shi, Zhonglin Jia

{"title":"Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes","authors":"Jialin Sun, Mujia Li, Huaqin Sun, Ziyuan Lin, Bing Shi, Zhonglin Jia","doi":"10.1038/s10038-024-01222-z","DOIUrl":"10.1038/s10038-024-01222-z","url":null,"abstract":"Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models. We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown. Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA. Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"139-144"},"PeriodicalIF":3.5,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model 在斑马鱼模型中再现人类 ACTA2 变体的心脏表现。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-02-05 DOI: 10.1038/s10038-024-01221-0

Wulan Apridita Sebastian, Masanori Inoue, Nobuyuki Shimizu, Ryosuke Sato, Saori Oguri, Tomoyo Itonaga, Shintaro Kishimoto, Hiroshi Shiraishi, Toshikatsu Hanada, Kenji Ihara

{"title":"Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model","authors":"Wulan Apridita Sebastian, Masanori Inoue, Nobuyuki Shimizu, Ryosuke Sato, Saori Oguri, Tomoyo Itonaga, Shintaro Kishimoto, Hiroshi Shiraishi, Toshikatsu Hanada, Kenji Ihara","doi":"10.1038/s10038-024-01221-0","DOIUrl":"10.1038/s10038-024-01221-0","url":null,"abstract":"The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"133-138"},"PeriodicalIF":3.5,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01221-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139692029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability 新型复合杂合ABCA2变体会导致IDPOGSA，这是一种表型多变的智障综合征。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-01-17 DOI: 10.1038/s10038-024-01219-8

Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

{"title":"Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability","authors":"Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-024-01219-8","DOIUrl":"10.1038/s10038-024-01219-8","url":null,"abstract":"The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA). In this study, we identified novel compound heterozygous ABCA2 variants (NM_001606.5:c.[5300–17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"163-167"},"PeriodicalIF":3.5,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene 关于因 FLAD1 和 ETFDH 基因变异导致核黄素反应性多酰基-CoA 脱氢缺乏症的比较研究。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-01-17 DOI: 10.1038/s10038-023-01216-3

Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, Chuanzhu Yan

{"title":"A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene","authors":"Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, Chuanzhu Yan","doi":"10.1038/s10038-023-01216-3","DOIUrl":"10.1038/s10038-023-01216-3","url":null,"abstract":"Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"125-131"},"PeriodicalIF":3.5,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology 利用深度学习技术对全基因组和复杂基因组区域进行基因型推算的方法。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-01-15 DOI: 10.1038/s10038-023-01213-6

Tatsuhiko Naito, Yukinori Okada

{"title":"Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology","authors":"Tatsuhiko Naito, Yukinori Okada","doi":"10.1038/s10038-023-01213-6","DOIUrl":"10.1038/s10038-023-01213-6","url":null,"abstract":"The imputation of unmeasured genotypes is essential in human genetic research, particularly in enhancing the power of genome-wide association studies and conducting subsequent fine-mapping. Recently, several deep learning-based genotype imputation methods for genome-wide variants with the capability of learning complex linkage disequilibrium patterns have been developed. Additionally, deep learning-based imputation has been applied to a distinct genomic region known as the major histocompatibility complex, referred to as HLA imputation. Despite their various advantages, the current deep learning-based genotype imputation methods do have certain limitations and have not yet become standard. These limitations include the modest accuracy improvement over statistical and conventional machine learning-based methods. However, their benefits include other aspects, such as their “reference-free” nature, which ensures complete privacy protection, and their higher computational efficiency. Furthermore, the continuing evolution of deep learning technologies is expected to contribute to further improvements in prediction accuracy and usability in the future.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"481-486"},"PeriodicalIF":2.6,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-023-01213-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling 通过适应性取样检测芳香族 L-氨基酸脱羧酶缺乏症中隐藏的内含子 DDC 变异。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-01-12 DOI: 10.1038/s10038-023-01217-2

Eriko Koshimizu, Mitsuhiro Kato, Kazuharu Misawa, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto

{"title":"Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling","authors":"Eriko Koshimizu, Mitsuhiro Kato, Kazuharu Misawa, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto","doi":"10.1038/s10038-023-01217-2","DOIUrl":"10.1038/s10038-023-01217-2","url":null,"abstract":"Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter disorder caused by pathogenic DOPA decarboxylase (DDC) variants. We previously reported Japanese siblings with AADC deficiency, which was confirmed by the lack of enzyme activity; however, only a heterozygous missense variant was detected. We therefore performed targeted long-read sequencing by adaptive sampling to identify any missing variants. Haplotype phasing and variant calling identified a novel deep intronic variant (c.714+255 C > A), which was predicted to potentially activate the noncanonical splicing acceptor site. Minigene assay revealed that wild-type and c.714+255 C > A alleles had different impacts on splicing. Three transcripts, including the canonical transcript, were detected from the wild-type allele, but only the noncanonical cryptic exon was produced from the variant allele, indicating that c.714+255 C > A was pathogenic. Target long-read sequencing may be used to detect hidden pathogenic variants in unresolved autosomal recessive cases with only one disclosed hit variant.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"153-157"},"PeriodicalIF":3.5,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139432652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy CRYAB止损变体导致罕见的综合征扩张型心肌病伴先天性白内障：扩大α-B晶体病的表型和突变谱。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-01-12 DOI: 10.1038/s10038-023-01218-1

Changhee Ha, Darae Kim, Minjung Bak, Jong-Ho Park, Young-gon Kim, Ja-Hyun Jang, Jong-Won Kim, Jin-Oh Choi, Mi-Ae Jang

{"title":"CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy","authors":"Changhee Ha, Darae Kim, Minjung Bak, Jong-Ho Park, Young-gon Kim, Ja-Hyun Jang, Jong-Won Kim, Jin-Oh Choi, Mi-Ae Jang","doi":"10.1038/s10038-023-01218-1","DOIUrl":"10.1038/s10038-023-01218-1","url":null,"abstract":"Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype. Dilated cardiomyopathy (DCM) is a disorder with a highly heterogeneous genetic etiology involving more than 60 causative genes, hindering genetic diagnosis. In this study, we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant in NM_001289808.2:c.527A>G of CRYAB in one patient. The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues, p.(Ter176TrpextTer19), which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin. The proband, diagnosed with DCM at age 32, had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms. He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant. This study expands the mutational spectrum of CRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"159-162"},"PeriodicalIF":3.5,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations IQSEC2 的 C 端截断：对突触定位、鸟嘌呤核苷酸交换因子活性和神经系统表现的影响

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-01-10 DOI: 10.1038/s10038-023-01210-9

Moeko Nakashima, Tomoko Shiroshima, Masahiro Fukaya, Takeyuki Sugawara, Hiroyuki Sakagami, Kazuki Yamazawa

{"title":"C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations","authors":"Moeko Nakashima, Tomoko Shiroshima, Masahiro Fukaya, Takeyuki Sugawara, Hiroyuki Sakagami, Kazuki Yamazawa","doi":"10.1038/s10038-023-01210-9","DOIUrl":"10.1038/s10038-023-01210-9","url":null,"abstract":"IQSEC2 gene on chromosome Xq11.22 encodes a member of guanine nucleotide exchange factor (GEF) protein that is implicated in the activation of ADP-ribosylation factors (Arfs) at the postsynaptic density (PSD), and plays a crucial role in synaptic transmission and dendritic spine formation. Alterations in IQSEC2 have been linked to X-linked intellectual developmental disorders including epilepsy and behavioral abnormalities. Of interest, truncating variants at the C-terminus of IQSEC2 can cause severe phenotypes, akin to truncating variants located in other regions. Here, we present a 5-year-old boy with severe intellectual disability and progressive epilepsy. The individual carried a nonsense variant p.Q1227* in the last exon of the IQSEC2 gene that was supposed to escape nonsense-mediated mRNA decay, thereby leading to a translation of C-terminus truncated IQSEC2 protein with residual activity. The functional analyses showed that the GEF activity of IQSEC2 Q1227* was compromised, and that the IQSEC2 Q1227* lacked preferential synaptic localization due to the absence of functional domains for binding to scaffolding proteins in the PSD. The impaired GEF activity and disrupted synaptic localization of the mutant IQSEC2 protein could impact dendritic and spine development in neurons, potentially explaining the patient’s severe neurological manifestations. Our findings indicate that C-terminal truncations in IQSEC2, previously not well-characterized, may have significant pathogenic implications.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"119-123"},"PeriodicalIF":3.5,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139413203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of protein structure and AI 预测蛋白质结构和人工智能

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-01-04 DOI: 10.1038/s10038-023-01215-4

Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi

引用次数: 0