Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

被引：45

作者：

Li, Lin ^{[1
,2
]}

Ghorbani, Mohammad ^{[1
,2
]}

Weisz-Hubshman, Monika ^{[3
,4
,5
]}

Rousseau, Justine ^{[6
]}

Thiffault, Isabelle ^{[7
,8
,9
]}

Schnur, Rhonda E. ^{[10
,11
]}

Breen, Catherine ^{[12
]}

Oegema, Renske ^{[13
]}

Weiss, Marjan M. M. ^{[14
]}

Waisfisz, Quinten ^{[14
]}

Welner, Sara ^{[15
]}

Kingston, Helen ^{[12
]}

Hills, Jordan A. ^{[16
]}

Boon, Elles M. J. ^{[14
]}

Basel-Salmon, Lina ^{[3
,4
,5
,17
]}

Konen, Osnat ^{[5
,18
]}

Goldberg-Stern, Hadassa ^{[5
,19
,20
]}

Bazak, Lily ^{[4
,5
]}

Tzur, Shay ^{[21
,22
]}

Jin, Jianliang ^{[1
,2
,23
]}

Bi, Xiuli ^{[1
,2
]}

Bruccoleri, Michael ^{[1
,2
]}

McWalter, Kirsty ^{[11
]}

Cho, Megan T. ^{[11
]}

Scarano, Maria ^{[10
]}

Schaefer, G. Bradley ^{[16
]}

Brooks, Susan S. ^{[15
]}

Hughes, Susan Starling ^{[7
,8
,9
]}

van Gassen, K. L., I ^{[13
]}

van Hagen, Johanna M. ^{[14
]}

Pandita, Tej K. ^{[24
]}

Agrawal, Pankaj B. ^{[25
,26
]}

Campeau, Philippe M. ^{[6
]}

Yang, Xiang-Jiao ^{[1
,2
,27
,28
]}

机构：

[1] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ, Canada

[2] McGill Univ, Dept Med, Montreal, PQ, Canada

[3] Schneider Childrens Med Ctr Israel, Pediat Genet Unit, Petah Tiqwa, Israel

[4] Rabin Med Ctr, Raphael Recanati Genet Inst, Petah Tiqwa, Israel

[5] Tel Aviv Univ, Sacker Fac Med, Tel Aviv, Israel

[6] Univ Montreal, CHU St Justine Hosp, Paediat Dept, Montreal, PQ, Canada

[7] Childrens Mercy Hosp, Ctr Pediat Genom Med, Kansas City, MO 64108 USA

[8] Childrens Mercy Hosp, Div Clin Genet, Kansas City, MO 64108 USA

[9] Univ Missouri, Fac Med, Kansas City, MO 64110 USA

[10] Cooper Univ Hlth Care, Div Genet, Camden, NJ USA

[11] GeneDx, Gaithersburg, MD USA

[12] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England

[13] Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands

[14] Univ Amsterdam, Dept Clin Genet, Med Ctr, Amsterdam, Netherlands

[15] State Univ New Jersey, Rutgers Robed Wood Johnson Med Sch, Div Pediat Med Genet, New Brunswick, NJ USA

[16] Univ Arkansas Med Sci, Little Rock, AR 72205 USA

[17] Rabin Med Ctr, Felsenstein Med Res Ctr, Petah Tiqwa, Israel

[18] Schneider Childrens Med Ctr Israel, Imaging Dept, Petah Tiqwa, Israel

[19] Schneider Med Ctr, Epilepsy Unit, Petah Tiqwa, Israel

[20] Schneider Med Ctr, EEG Lab, Petah Tiqwa, Israel

[21] Technion Israel Inst Technol, Rappaport Fac Med & Res Inst, Lab Mol Med, Haifa, Israel

[22] Emedgene Technol, Genom Res Dept, Tel Aviv, Israel

[23] Nanjing Med Univ, Dept Human Anat, Key Lab Aging & Dis, Res Ctr Bone & Stem Cells, Nanjing, Jiangsu, Peoples R China

[24] Houston Methodist Res Inst, Dept Radiat Oncol, Houston, TX USA

[25] Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Newborn Med, Boston, MA 02115 USA

[26] Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA

[27] McGill Univ, Dept Biochem, Hlth Ctr, Montreal, PQ, Canada

[28] McGill Univ, Dept Med, Hlth Ctr, Montreal, PQ, Canada

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 03期

基金：

美国国家卫生研究院; 英国惠康基金; 加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

NEURAL STEM-CELLS; HISTONE ACETYLTRANSFERASE; DOSAGE COMPENSATION; MALES ABSENT; HBO1; ACETYLTRANSFERASE; HEMATOPOIETIC STEM; H4K16; ACETYLATION; H4; LYSINE-16; MOF; PROTEIN;

D O I：

10.1172/JCI131145

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

引用

页码：1431 / 1445

页数：15

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