Genetic defects in pediatric-onset adrenal insufficiency in Japan

Amano, Nobuyuki; Narumi, Shunji; Hayashi, Masako; Takagi, Masaki; Imai, Ken; Nakamura, Takao; Hachiya, Rumi; Sasaki, Goro; Homma, Keiko; Ishii, Tomohiro; Hasegawa, Tomonobu

doi:10.1530/eje-17-0027

Cited by 36 publications

(30 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human SAMD9 (hSAMD9), human SAMD9L (hSAMD9L), and mouse SAMD9L (mSAMD9L) are all capable of blocking the replication of poxvirus mutants that lack K1L-and C7L-like genes (23)(24)(25). SAMD9&L are also recognized as tumor suppressors (27)(28)(29), and germ line mutations of human SAMD9 or SAMD9L are associated with multisystem disorders characterized by immunodeficiency and predisposition to hematological malignancies (30)(31)(32)(33)(34)(35). In this study, we investigated whether CP77 functions similarly to K1 and C7 by directly targeting SAMD9 or SAMD9L.…”

mentioning

confidence: 99%

Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Zhang

Meng

Townsend

et al. 2019

J Virol

View full text Add to dashboard Cite

Orthopoxviruses (OPXVs) have a broad host range in mammalian cells, but Chinese hamster ovary (CHO) cells are nonpermissive for vaccinia virus (VACV).Here, we revealed a species-specific difference in host restriction factor SAMD9L as the cause for the restriction and identified orthopoxvirus CP77 as a unique inhibitor capable of antagonizing Chinese hamster SAMD9L (chSAMD9L). Two known VACV inhibitors of SAMD9 and SAMD9L (SAMD9&L), K1 and C7, can bind human and mouse SAMD9&L, but neither can bind chSAMD9L. Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 knockout of chSAMD9L from CHO cells removed the restriction for VACV, while ectopic expression of chSAMD9L imposed the restriction for VACV in a human cell line, demonstrating that chSAMD9L is a potent restriction factor for VACV. In contrast to K1 and C7, cowpox virus CP77 can bind chSAMD9L and rescue VACV replication in cells expressing chSAMD9L, indicating that CP77 is yet another SAMD9L inhibitor but has a unique specificity for chSAMD9L. Binding studies showed that the N-terminal 382 amino acids of CP77 were sufficient for binding chSAMD9L and that both K1 and CP77 target a common internal region of SAMD9L. Growth studies with nearly all OPXV species showed that the ability of OPXVs to antagonize chSAMD9L correlates with CP77 gene status and that a functional CP77 ortholog was maintained in many OPXVs, including monkeypox virus. Our data suggest that a species-specific difference in rodent SAMD9L poses a barrier for cross-species OPXV infection and that OPXVs have evolved three SAMD9&L inhibitors with different specificities to overcome this barrier. IMPORTANCE Several OPXV species, including monkeypox virus and cowpox virus, cause zoonotic infection in humans. They are believed to use wild rodents as the reservoir or intermediate hosts, but the host or viral factors that are important for OPXV host range in rodents are unknown. Here, we showed that the abortive replication of several OPXV species in a Chinese hamster cell line was caused by a species-specific difference in the host antiviral factor SAMD9L, suggesting that SAMD9L divergence in different rodent species poses a barrier for cross-species OPXV infection. While the Chinese hamster SAMD9L could not be inhibited by two previously identified OPXV inhibitors of human and mouse SAMD9&L, it can be inhibited by cowpox virus CP77, indicating that OPXVs encode three SAMD9&L inhibitors with different specificities. Our data suggest that OPXV host range in broad rodent species depends on three SAMD9&L inhibitors with different specificities. KEYWORDS host range, host restriction factor, poxvirus, vaccinia virus T he Orthopoxvirus (OPXV) genus of the Poxviridae family consists of more than 10 closely related species, including the human pathogen variola virus (VARV) (the causative agent for smallpox), the smallpox vaccine vaccinia virus (VACV), and the emerging Citation Zhang F, Meng X, Townsend MB, Satheshkumar PS, Xiang Y. 2019. Identification of CP77 as the third orthopoxvirus SAMD9...

show abstract

mentioning

confidence: 99%

Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Zhang

Meng

Townsend

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

“…to identify deep intronic variants and epigenetic changes [29][30][31][32]. Table 4 The gene spectrum of uncharacterized PAI in other ethnic groups…”

Section: Discussionmentioning

confidence: 99%

“…Methods STAR NR0B1 SMAD9 AAAS NNT MC2R CDKN1C AIRE CYP11A1 MRAP NR5A1 ABCD1 CYP11B1 Japan [32] targeted gene sequence 19 18 7 2 2 1 1 -0 0 0 --Canada [31] targeted gene sequence…”

Section: Countrymentioning

confidence: 99%

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. Results Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p. 279GfsX17) and c.651 + 2T > G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p. 108S > X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399 + 1G > A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein. Conclusions We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.

show abstract

“…TART, gonadal insufficiency), and heart diseases. Proper diagnosis of unknown cases of PAI is therefore important to adequately control long-term treatment and follow-up in such patients (2,3,4,5).…”

Section: Skin Manifestationmentioning

confidence: 99%

“…The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress (4,5).…”

mentioning

confidence: 99%

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children

Kamrath

2020

European Journal of Endocrinology

View full text Add to dashboard Cite

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients. Gonadal dysfunctionDeficient or reduced fetal testicular steroidogenesis results in phenotypically normal female genitalia or undervirilized male genitalia in patients with a 46,XY karyotype (46,XY disorder of sex development (DSD)) in the subsequent CAH

show abstract

Genetic defects in pediatric-onset adrenal insufficiency in Japan

Cited by 36 publications

References 31 publications

Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children

Contact Info

Product

Resources

About