研究者詳細 - 鳴海　覚志

論文 - 鳴海　覚志

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乳児期早期からの間質性肺炎と多臓器石灰化を認めI型インターフェロン異常症を疑った男児例

相原健志, 石川尊士, 岡井真史, 中尾寛, 玉井直敬, 肥沼悟郎, 木戸口千晶, 庄司健介, 西健太朗, 太田知子, 曽根田京子, 大北恵子, 山田全毅, 今留謙一, 鳴海覚志, 今井耕輔, 小野寺雅史, 窪田満, 石黒精, 河合利尚

日本小児科学会雑誌（(公社)日本小児科学会） 126 （ 2 ） 284 - 284 2022年02月

ISSN 0001-6543

Discovery of MIRAGE syndrome

Narumi S.

Pediatrics International （Pediatrics International） 64 （ 1 ） e15283 2022年01月

ISSN 13288067

Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.

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Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review

Sugisawa C., Taniyama M., Sato T., Takahashi Y., Hasegawa T., Narumi S.

Endocrine Journal （Endocrine Journal） 69 （ 7 ） 831 - 838 2022年

ISSN 09188959

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that causes gonadotropin-releasing hormone (GnRH) deficiency and sexual immaturity. CHH may accompany an abnormal sense of smell (Kallmann syndrome, KS) or no such manifestation (normosmic-CHH). This unusual combination of manifestations is explained by the fact that GnRH neurons originate in the olfactory placode and migrate to the forebrain during embryogenesis. We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. He was noticed to have sexual immaturity (small testes with no pubic hair) at age 20 years, when diabetic ketoacidosis developed. Basal and GnRH-stimulated levels of LH (1.0→12.0 IU/L) and FSH (1.9→6.1 IU/L) were detectable but low. The results of the T&T olfactometer and the Alinamin test were definitely normal, with an anatomically normal olfactory system on MRI. Sequencing of 22 CHH-related genes was performed, and compound heterozygous PROKR2 variants were identified: one was a previously known loss-of-function variant (p.Trp178Ser) and the other was a nonsense variant (p.Trp212*). Through a literature review, we found 22 patients (including our patient) with CHH due to biallelic PROKR2 variants, which led us to recognize that most of the patients (86%) were diagnosed with KS. Clinical observations in this study indicate that, even though they have CHH, biallelic PROKR2 variant carriers may have a normal olfactory system as well as presumably normal migration of GnRH neurons. This suggests that the PROK2-PROKR2 pathway affects the function of GnRH neurons after their migration.

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An improved macromolecular crowding sensor CRONOS for detection of crowding changes in membrane-less organelles under stressed conditions

Miyagi T., Yamanaka Y., Harada Y., Narumi S., Hayamizu Y., Kuroda M., Kanekura K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 583 29 - 34 2021年12月

ISSN 0006291X

Membrane-less organelles (MLOs) formed by liquid-liquid phase separation (LLPS) play pivotal roles in biological processes. During LLPS, proteins and nucleotides are extremely condensed, resulting in changes in their conformation and biological functions. Disturbed LLPS homeostasis in MLOs is thought to associate with fatal diseases such as amyotrophic lateral sclerosis. Therefore, it is important to detect changes in the degree of crowding in MLOs. However, it has not been investigated well due to the lack of an appropriate method. To address this, we developed a genetically encoded macromolecular crowding sensor CRONOS (crowding sensor with mNeonGreen and mScarlet-I) that senses the degree of macromolecular crowding in MLOs using a fluorescence resonance energy transfer (FRET) system. CRONOS is a bright biosensor with a wide dynamic range and successfully detects changes in the macromolecular volume fraction in solution. By fusing to the scaffold protein of each MLO, we delivered CRONOS to MLO of interest and detected previously undescribed differences in the degree of crowding in each MLO. CRONOS also detected changes in the degree of macromolecular crowding in nucleolus induced by environmental stress or inhibition of transcription. These findings suggest that CRONOS can be a useful tool for the determination of molecular crowding and detection of pathological changes in MLOs in live cells.

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The case of a patient with MIRAGE syndrome with familial dysautonomia-like symptoms

Kawashima-Sonoyama Y., Okuno K., Dohmoto T., Tanase-Nakao K., Narumi S., Namba N.

Human Genome Variation （Human Genome Variation） 8 （ 1 ） 27 - 27 2021年12月

ISSN 2054-345X

We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in a girl with a new pathogenic SAMD9 variant (p.F437S), who was initially considered to have familial dysautonomia (FD)-like disease due to increased levels of catecholamine metabolites. Functional analyses of F437S-SAMD9 were performed, showing characteristics of disease-causing variants. This new SAMD9 variant (p.F437S) also causes MIRAGE syndrome.

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ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance

Kagami M., Hara-Isono K., Matsubara K., Nakabayashi K., Narumi S., Fukami M., Ohkubo Y., Saitsu H., Takada S., Ogata T.

Clinical Epigenetics （Clinical Epigenetics） 13 （ 1 ） 119 - 119 2021年12月

ISSN 18687075

Background: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. Results: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. Conclusions: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.

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Hereditary paraganglioma presenting with atypical symptoms: Case report

Eguchi S., Ono R., Sato T., Yada K., Umehara N., Narumi S., Ichihashi Y., Nozaki T., Kanomata N., Hasegawa T., Ozawa M., Hasegawa D.

Medicine (United States) （Medicine (United States)） 100 （ 46 ） e27888 2021年11月

ISSN 00257974

Rationale:Paraganglioma (PGL), an extra-adrenal pheochromocytoma, is a rare tumor, especially in children. While hypersecretion of catecholamines causes the classic triad of headaches, palpitations, and profuse sweating, prompt diagnosis is still challenging.Patient concerns:For 7 months, an 8-year-old boy complained of polyuria and weight loss, followed by proteinuria and headache for 1 month prior to admission. He was admitted to our hospital due to an afebrile seizure.Diagnosis:His blood pressure remained markedly elevated even after cessation of the convulsion. Magnetic resonance imaging of the brain revealed posterior reversible encephalopathy syndrome. Abdominal computed tomography showed a mass lesion encasing the left renal artery, measuring 41 mm in length along its major axis. The plasma and urine levels of normetanephrine were elevated. Additionally, iodine-123-metaiodobenzylguanidine scintigraphy showed an abnormal uptake in the abdominal mass with no evidence of metastasis. Based on these findings, we tentatively diagnosed him with PGL.Intervention:Substantial alpha-and beta-blocking procedures were performed, followed by a tumor resection and an extended left nephrectomy on day 31 of hospitalization. Pathological findings confirmed the diagnosis of PGL.Outcome:The postoperative course was uneventful, and his blood pressure normalized without the use of antihypertensive agents. Genetic testing revealed a known SDHB germline mutation. The same mutation was also detected on his father and paternal grandfather without any history of hypertension or malignant tumor.Lesson:It remains challenging to diagnose pheochromocytoma/paraganglioma (PPGL) promptly because PPGL can present with a variety of symptoms. Preceding symptoms of the presented case might be caused by PGL. Although PPGL is a rare disease, especially in children, it should be considered in differential diagnosis when various unexplained symptoms persist.

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Phase separation and toxicity of c9orf72 poly(Pr) depends on alternate distribution of arginine

Chen C., Yamanaka Y., Ueda K., Li P., Miyagi T., Harada Y., Tezuka S., Narumi S., Sugimoto M., Kuroda M., Hayamizu Y., Kanekura K.

Journal of Cell Biology （Journal of Cell Biology） 220 （ 11 ） e202103160 2021年11月

査読有り, ISSN 00219525

Arg (R)-rich dipeptide repeat proteins (DPRs; poly(PR): Pro-Arg and poly(GR): Gly-Arg), encoded by a hexanucleotide expansion in the C9ORF72 gene, induce neurodegeneration in amyotrophic lateral sclerosis (ALS). Although R-rich DPRs undergo liquid–liquid phase separation (LLPS), which affects multiple biological processes, mechanisms underlying LLPS of DPRs remain elusive. Here, using in silico, in vitro, and in cellulo methods, we determined that the distribution of charged Arg residues regulates the complex coacervation with anionic peptides and nucleic acids. Proteomic analyses revealed that alternate Arg distribution in poly(PR) facilitates entrapment of proteins with acidic motifs via LLPS. Transcription, translation, and diffusion of nucleolar nucleophosmin (NPM1) were impaired by poly(PR) with an alternate charge distribution but not by poly(PR) variants with a consecutive charge distribution. We propose that the pathogenicity of R-rich DPRs is mediated by disturbance of proteins through entrapment in the phase-separated droplets via sequence-controlled multivalent protein–protein interactions.

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【小児遺伝子疾患事典】免疫疾患 SAMD9(関連疾患:MIRAGE症候群)

中尾佳奈子, 鳴海覚志

小児科診療（(株)診断と治療社） 84 （ 11 ） 1683 - 1684 2021年11月

ISSN 0386-9806

Role of Liquid-Liquid Separation in Endocrine and Living Cells

Akiba K., Katoh-Fukui Y., Yoshida K., Narumi S., Miyado M., Hasegawa Y., Fukami M.

Journal of the Endocrine Society （Journal of the Endocrine Society） 5 （ 10 ） bvab126 2021年10月

Context: Recent studies have revealed that every eukaryotic cell contains several membraneless organelles created via liquid-liquid phase separation (LLPS). LLPS is a physical phenomenon that transiently compartmentalizes the subcellular space and thereby facilitates various biological reactions. LLPS is indispensable for cellular functions; however, dysregulated LLPS has the potential to cause irreversible protein aggregation leading to degenerative disorders. To date, there is no systematic review on the role of LLPS in endocrinology. Evidence acquisition: We explored previous studies which addressed roles of LLPS in living cells, particularly from the viewpoint of endocrinology. To this end, we screened relevant literature in PubMed published between 2009 and 2021 using LLPS-associated keywords including "membraneless organelle,""phase transition,"and "intrinsically disordered,"and endocrinological keywords such as "hormone,""ovary,""androgen,"and "diabetes."We also referred to the articles in the reference lists of identified papers. Evidence synthesis: Based on 67 articles selected from 449 papers, we provided a concise overview of the current understanding of LLPS in living cells. Then, we summarized recent articles documenting the physiological or pathological roles of LLPS in endocrine cells. Conclusions: The discovery of LLPS in cells has resulted in a paradigm shift in molecular biology. Recent studies indicate that LLPS contributes to male sex development by providing a functional platform for SOX9 and CBX2 in testicular cells. In addition, dysregulated LLPS has been implicated in aberrant protein aggregation in pancreatic β-cells, leading to type 2 diabetes. Still, we are just beginning to understand the significance of LLPS in endocrine cells.

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A case report with functional characterization of a HNF1B mutation (P.Leu168Pro) causing MODY5

Yoshida K., Mushimoto Y., Tanase-Nakao K., Akiba K., Ishii K., Urakami T., Sugihara S., Kikuchi T., Fukami M., Narumi S.

Clinical Pediatric Endocrinology （Clinical Pediatric Endocrinology） 30 （ 4 ） 179 - 185 2021年10月

ISSN 09185739

We previously performed next-generation sequencing-based genetic screening in patients with autoantibodynegative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here, we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

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Acquired uniparental disomy of chromosome 7 in a patient with mirage syndrome that veiled a pathogenic samd9 variant

Tanase-Nakao K., Kawai M., Wada K., Kagami M., Narumi S.

Clinical Pediatric Endocrinology （Clinical Pediatric Endocrinology） 30 （ 4 ） 163 - 169 2021年10月

ISSN 09185739

Gain-of-function variants in SAMD9, which resides on chromosome 7, cause MIRAGE syndrome that is associated with congenital adrenal insufficiency and gonadal dysgenesis. We previously reported a Japanese patient with MIRAGE syndrome carrying a de novo heterozygous SAMD9 variant (p.Ala1479Ser). In this study, we confirmed the pathogenicity of Ala1479Ser-SAMD9 in vitro. Genetic study results revealed an atypically low variant allele frequency (26%) and we suspected of genomic rearrangement(s) involving chromosome 7. Single nucleotide polymorphism (SNP) array and short tandem repeat analysis showed presence of mosaic maternal isodisomic uniparental disomy 7 (UPD7). Deep sequencing using DNA samples obtained at 0, 6, 10, and 25 mo of age revealed that the percentage of cells with UPD7 increased constantly from 6% to 82% over 25 mo, and this increase coincided with a decrease in the percentage of cells with p.Ala1479Ser from 94% to nearly undetectable levels. We further screened for low-allele-frequency and rare SAMD9 variants in eight patients with Silver-Russel syndrome and maternal UPD7; however, none of the patients harbored such a variant. In conclusion, our case demonstrates that genetic findings can vary considerably in patients with MIRAGE syndrome and that a comprehensive diagnostic approach, including SNP array and deep sequencing, is important in such cases.

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SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome

Shima H., Tokuhiro E., Okamoto S., Nagamori M., Ogata T., Narumi S., Nakamura A., Izumi Y., Jinno T., Suzuki E., Fukami M.

Journal of the Endocrine Society （Journal of the Endocrine Society） 5 （ 7 ） 1 - 7 2021年07月

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. Patients and Methods: A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. Results: Sequence analysis identified 2 heterozygous variants of SOX10 (c.1225G > T, p.Gly409∗ and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively. Conclusion: These results provide evidence that SOX10 haploinsufficiency accounts for a small percentage of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.

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Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46,XX ovotesticular disorder of sex development

Ushijima K., Ogawa Y., Terao M., Asakura Y., Muroya K., Hayashi M., Ishii T., Hasegawa T., Sekido R., Fukami M., Takada S., Narumi S.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 185 （ 4 ） 1067 - 1075 2021年04月

ISSN 15524825

SOX9, a transcription factor, is expressed in the undifferentiated XX and XY gonads. SRY induces significant upregulation of SOX9 expression in XY gonads. Loss-of-function SOX9 variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain-of-function (GoF) SOX9 variants have not been reported previously. We report the case of a 16-year-old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next-generation sequencing-based genetic screening for disorders of sex development led to the identification of a novel SOX9 variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K-SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype-SOX9. This GoF activity was not observed in the luciferase reporter containing Amh, the gene for anti-Müllerian hormone. We genetically engineered female mice (Sox9E50K/E50K), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel SOX9 variant with a promoter-specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF SOX9 variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.

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若年者バセドウ病のチアマゾール単独治療、チアマゾール+無機ヨウ素併用治療の有効性と安全性に関する多施設共同観察研究後ろ向きコホート研究

大江秀美, 南谷幹史, 荒田尚子, 長谷川奉延, 伊藤順庸, 猪俣弘明, 内野眞也, 鬼形和道, 佐藤浩一, 杉原茂孝, 長崎啓祐, 鳴海覚志, 長谷川行洋, 原田正平, 深田修司, 久門真子, 御前隆, 横谷進, 吉村弘, 金城さおり, 春名英典, 松下理恵, 宮田市郎, 三善陽子, 虫本雄一, 堀川玲子, 室谷浩二, 日本甲状腺学会小児甲状腺疾患診療委員会

日本内分泌学会雑誌（(一社)日本内分泌学会） 96 （ 4 ） 927 - 927 2021年04月

ISSN 0029-0661

若年者バセドウ病のチアマゾール単独治療、チアマゾール+無機ヨウ素併用治療の有効性と安全性に関する多施設共同観察研究後ろ向きコホート研究

日本内分泌学会雑誌（(一社)日本内分泌学会） 96 （ 4 ） 927 - 927 2021年04月

ISSN 0029-0661

先天性甲状腺機能低下症をきたすジスルフィド結合の消失を伴う新規甲状腺ペルオキシダーゼ変異の機能解析

谷古宇史芳, 諏訪内浩紹, 石川卓也, 伊藤真理子, 志熊淳平, 三輪隆, 酒井裕幸, 金蔵孝介, 鳴海覚志, 鈴木亮, 小田原雅人

日本内分泌学会雑誌（(一社)日本内分泌学会） 96 （ 4 ） 955 - 955 2021年04月

ISSN 0029-0661

A Case of Luscan-Lumish Syndrome: Possible Involvement of Enhanced GH Signaling

Suda K., Fukuoka H., Iguchi G., Kanie K., Fujita Y., Odake Y., Matsumoto R., Bando H., Ito H., Takahashi M., Chihara K., Nagai H., Narumi S., Hasegawa T., Ogawa W., Takahashi Y.

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 106 （ 3 ） 718 - 723 2021年03月

ISSN 0021972X

Context: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. Case Description: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. Conclusion: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

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Inactivation of a Frameshift TSH Receptor Variant Val711Phefs∗18 is Due to Acquisition of a Hydrophobic Degron

Sugisawa C., Ono M., Kashimada K., Hasegawa T., Narumi S.

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 106 （ 1 ） E265 - E272 2021年01月

ISSN 0021972X

Context: Inactivating variants of thyrotropin (thyroid-stimulating hormone; TSH) receptor (TSHR) cause congenital hypothyroidism. More than 60 such variants have been reported so far, most of which were located in the extracellular or transmembrane domain. Objective: We report the identification and characterization of a frameshift TSHR variant in the intracytoplasmic C-tail region. Methods: Sequencing of TSHR was performed in a patient with congenital hypothyroidism. The functionality of the identified variants was assessed by expressing TSHR in HEK293 cells and measuring TSH-dependent activation of the cAMP-response element-luciferase reporter. A series of systematic mutagenesis experiments were performed to characterize the frameshifted amino acid sequence. Results: The proband was heterozygous for a known TSHR variant (p.Arg519His) and a novel frameshift TSHR variant (p.Val711Phefs∗18), which removed 54 C-terminal residues and added a 17-amino acid frameshifted sequence. The loss of function of Val711Phefs∗18-TSHR was confirmed in vitro, but the function of Val711∗-TSHR was found to be normal. Western blotting showed the low protein expression of Val711Phefs∗18-TSHR. Fusion of the frameshift sequence to green fluorescent protein or luciferase induced inactivation of them, indicating that the sequence acted as a degron. A systematic mutagenesis study revealed that the density of hydrophobic residues in the frameshift sequence determined the stability. Eight additional frameshift TSHR variants that covered all possible shifted frames in C-tail were created, and another frameshift variant (Thr748Profs∗27) with similar effect was found. Conclusions: We characterized a naturally occurring frameshift TSHR variant located in C-tail, and provided a unique evidence that hydrophobicity in the C-terminal region of the receptor affects protein stability.

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Complete androgen insensitivity syndrome with accelerated onset of puberty due to a sertoli cell tumor

Izawa M., Hisamatsu E., Yoshino K., Yoshida M., Sato T., Narumi S., Hasegawa T., Hamajima T.

Clinical Pediatric Endocrinology （Clinical Pediatric Endocrinology） 30 （ 2 ） 99 - 104 2021年

ISSN 09185739

Complete androgen insensitivity syndrome (CAIS) is caused by mutations in the androgen receptor gene. Patients with this syndrome have a 46,XY karyotype, male gonads, and normal female external genitalia. While the pre-pubertal risk of developing gonadal tumors is low in these patients, it increases with age. Most gonadal tumors arise from germ cells; stromal cell tumors are uncommon. Herein, we report a CAIS patient with a feminizing Sertoli cell tumor. The patient presented at 8 yr of age with breast enlargement and growth acceleration, concomitant with elevated serum estradiol levels and suppressed serum gonadotropin levels; these findings were inconsistent with CAIS. The patient underwent gonadectomy at 10 yr of age, and histology demonstrated presence of a non-malignant Sertoli cell tumor in the right gonad. We conclude that this is the first reported case of CAIS with accelerated onset of puberty resulting from a Sertoli cell tumor.

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