Ankyrin Repeat Domain-containing Research Articles

Case report: Whole exome sequencing reveals a novel splicing variant of ANKRD17 gene in a Chinese male juvenile with developmental delay and transient tic disorder

BackgroundThe Ankyrin Repeat Domain Containing Protein 17 (ANKRD17, OMIM:615929) gene is a protein-coding gene associated with diseases such as Chopra-Amiel-Gordon Syndrome and Non-Specific Syndromic Intellectual Disability. The protein encoded by ANKRD17 gene belongs to the ankyrin repeat-containing protein family, which is one of the most widely existing protein domains that exclusively mediate protein-protein interactions. To date, the research and reports on the ANKRD17 gene are limited.Case presentationTrio whole exome sequencing (Trio-WES) was conducted on the proband and his unaffected parents to elucidate the genetic etiology in the proband, who was clinically diagnosed with developmental delay and other phenotypes. Subsequently, Sanger sequencing was employed for validation of the identified candidate variant. Furthermore, RNA analysis was utilized to ascertain the impact of the variant on splicing. The WES revealed a novel heterozygous ANKRD17 splicing variant (c.7248 + 1G>A) in the proband, but not detected in his unaffected parents. And the presence of the splicing variant of the ANKRD17 gene was valided by the Sanger sequencing subsequently. And the RNA analysis confirmed that the novel variant was predicted to result in loss of donor splice site, and the analysis at mRNA level confirmed that it leads to exon 32 skipping (r.7100_7278del179) and causes premature termination of translation to the protein (p.D2357fs), therefore is classified as pathogenic.ConclusionOur study reported a novel splicing variant in ANKRD17 gene, which may be associated with partial eating, frequent urination, and tic syndrome. This finding expands both the phenotypic and genotypic spectrum of ANKRD17 gene. Although there is currently no curative therapy available for ANKRD17 gene variants, a definitive diagnosis of its genetic etiology is significant for genetic counseling and family planning purposes. Furthermore, this is the first reported case of the ANKRD17 gene in China.

KANK3 mediates the p38 MAPK pathway to regulate the proliferation and invasion of lung adenocarcinoma cells

BackgroundLung adenocarcinoma (LUAD) is one of the major subtypes of lung cancer and is the most common cause of cancer deaths globally. The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been characterized as critical for regulating the capacity of cells to migrate and their anti-tumor drug sensitivity. The current research designs to explore the specific effects and potential regulatory molecular mechanism of KANK3 on LUAD cells. MethodTwo datasets (TCGA-LUAD and GSE116959) were analyzed to confirm the differently expressed genes. qRT-PCR was carried out to measure KANK3 level in LUAD tissue samples and adjacent non-cancerous tissue samples. Western blot assay was utilized to investigate the KANK3, p-p38 and p38 protein levels. MTT assay were employed to investigate the cell proliferation. Cell invasion and migration were assessed using Transwell and wound healing assay. ResultKANK3 was down-regulated in LUAD tissues and the expressions of KANK3 had a strong influence on prognosis of LUAD patients. Overexpression of KANK3 significantly inhibited， whereas KANK3 silencing observably enhanced the capacity of NCI-H1975 and PC-9 cells to proliferate, invade and migrate. GSEA showed that, differentially expressed genes which regulated by KANK3 enriched in cell adhesion, chemokine, focal adhesion or MAPK signaling pathway. Further experiments proved that KANK3 regulated LUAD cells proliferation and metastasis through p38 MAPK pathway. ConclusionKANK3 exerts antitumor effect in LUAD through regulation of p38 MAPK signaling pathway. These outcomes foreboded that KANK3 could be a novel therapeutic target for further study of LUAD.

PD15-01 KANK1 GENETIC AND GENOMIC ANOMALIES AFFECT GENITOURINARY (GU) DEVELOPMENT IN HUMANS

You have accessJournal of UrologyPediatric Urology I (PD15)1 Sep 2021PD15-01 KANK1 GENETIC AND GENOMIC ANOMALIES AFFECT GENITOURINARY (GU) DEVELOPMENT IN HUMANS Marisol O'Neill, and Dolores Lamb Marisol O'NeillMarisol O'Neill More articles by this author , and Dolores LambDolores Lamb More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001997.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 9p24.3 is a chromosome hotspot for human GU anomalies with micro-deletions or -duplications associated with ambiguous genitalia and gonadal dysgenesis. One gene in 9p24.3, DMRT1, is needed for normal testicular fetal development. Using array comparative genomic hybridization (aCGH) together with retrospective literature/database analysis, locus mapping identified 60 patients with 9p24.3 CNVs of 37 duplications and 23 microdeletions. 50 of these patients had disorders of sexual differentiation, 7 had congenital anomalies of the kidney and urinary tract (CAKUT). We identified a second gene candidate in the minimal overlap region of 9p24.3 5' to DMRT1 that encompasses KN Motif and Ankyrin Repeat Domain Containing Protein 1 (KANK1). We used human and mouse models to test the hypothesis that genetic and genomic defects of KANK1 also resulted in anomalies of the external genitalia and CAKUT. METHODS: A mouse model of haploinsufficiency was generated using CRISPR-Cas9 to delete Kank1 and mice phenotyped. Penile and renal anomalies were defined by micro-CT analysis. Patients with upper and lower tract genitourinary birth defects underwent phenotypic analysis, genetic and genomic analysis by aCGH and whole exome sequencing. RESULTS: A mouse model of Kank1 haploinsufficiency exhibited renal dysfunction, penile anomalies and subfertility. KANK1 genetic variants were identified by Whole Exome Sequencing (WES) in patients with GU anomalies-2 had novel variants; one individual with an absent cervix, vaginal atresia and two novel variants resulting in nonsynonymous changes of two consecutive amino acids (p.C1187F and p.N118Y) both predicted to be deleterious. 14 individuals were identified with 10 rare variants, five of which (rs61737971, rs148744436, rs143675911, rs74458120, rs370051574) were present in individuals with CAKUT, renal insufficiency, focal segmental glomerulosclerosis, abnormal reproductive track development, hypospadias, bladder exstrophy- glomerular fibrosis, renal dysfunction, penile anomalies were also present in the Kank1 haploinsufficient mouse models. CONCLUSIONS: This study identifies a novel mechanism that underlies some GU birth defects which are usually surgically repaired with the etiology defined as idiopathic. This study identified renal dysfunction and a potentially severe kidney phenotype, as well as developmental anomalies of the penis caused by KANK1 haploinsufficiency in humans & mouse models. Source of Funding: T32 DK007763 (MO was a trainee) & R01DK078121 from NIDDK & Frederick J. and Theresa Dow Wallace Fund of the NY Community Trust (awarded to DJL) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e272-e272 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marisol O'Neill More articles by this author Dolores Lamb More articles by this author Expand All Advertisement Loading ...

KANK family proteins in cancer.

The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.