Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

被引：17

作者：

Marbach, Felix ^{[1
]}

Stoyanov, Georgi ^{[2
]}

Erger, Florian ^{[2
,3
]}

Stratakis, Constantine A. ^{[4
]}

Settas, Nikolaos ^{[4
]}

London, Edra ^{[4
]}

Rosenfeld, Jill A. ^{[5
,6
,22
]}

Torti, Erin ^{[7
]}

Haldeman-Englert, Chad ^{[8
]}

Sklirou, Evgenia ^{[9
]}

Kessler, Elena ^{[9
]}

Ceulemans, Sophia ^{[10
]}

Nelson, Stanley F. ^{[11
,31
]}

Martinez-Agosto, Julian A. ^{[11
,31
]}

Palmer, Christina G. S. ^{[11
,12
,13
,31
]}

Signer, Rebecca H. ^{[11
,31
]}

Acosta, Maria T. ^{[17
]}

Adam, Margaret ^{[18
,19
]}

Adams, David R. ^{[17
]}

Agrawal, Pankaj B. ^{[20
,21
]}

Alejandro, Mercedes E. ^{[22
]}

Alvey, Justin ^{[23
]}

Amendola, Laura ^{[18
,19
]}

Andrews, Ashley ^{[23
]}

Ashley, Euan A. ^{[24
]}

Azamian, Mahshid S. ^{[22
]}

Bacino, Carlos A. ^{[22
]}

Bademci, Guney ^{[25
]}

Baker, Eva ^{[17
]}

Balasubramanyam, Ashok ^{[22
]}

Baldridge, Dustin ^{[26
,27
]}

Bale, Jim ^{[23
]}

Bamshad, Michael ^{[18
,19
]}

Barbouth, Deborah ^{[25
]}

Bayrak-Toydemir, Pinar ^{[23
]}

Beck, Anita ^{[18
,19
]}

Beggs, Alan H. ^{[20
,21
]}

Behrens, Edward ^{[28
,29
]}

Bejerano, Gill ^{[24
]}

Bennett, Jimmy ^{[18
,19
]}

Berg-Rood, Beverly ^{[18
,19
]}

Bernstein, Jonathan A. ^{[24
]}

Berry, Gerard T. ^{[20
,21
]}

Bican, Anna ^{[30
]}

Bivona, Stephanie ^{[25
]}

Blue, Elizabeth ^{[18
,19
]}

Bohnsack, John ^{[23
]}

Bonnenmann, Carsten ^{[17
]}

Bonner, Devon ^{[24
]}

Botto, Lorenzo ^{[23
]}

机构：

[1] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany

[2] Univ Cologne, Fac Med, Cologne, Germany

[3] Univ Hosp Cologne, Inst Human Genet, Cologne, Germany

[4] Eun Kennedy Shriver Natl Inst Child Hlth & Human, Sect Endocrinol & Genet, Bethesda, MD USA

[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[6] Baylor Genet Lab, Houston, TX USA

[7] GeneDX, Gaithersburg, MD USA

[8] Mission Fullerton Genet Ctr, Asheville, NC USA

[9] Univ Pittsburgh, Dept Pediat, Sch Med, Pittsburgh, PA USA

[10] Rady Childrens Hosp, Genet Dysmorphol, San Diego, CA USA

[11] David Geffen Sch Med UCLA, Dept Human Genet, Los Angeles, CA USA

[12] David Geffen Sch Med UCLA, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA

[13] UCLA, Inst Soc & Genet, Los Angeles, CA USA

[14] Washington Univ, Dept Pediat, Div Genet & Gen Med, Sch Med, St Louis, MO USA

[15] Newcastle Univ, Biosci Inst, Fac Med Sci, Int Ctr Life, Biomed West Wing,Times Sq, Newcastle Upon Tyne, Tyne & Wear, England

[16] INTEGRIS Pediat Neurol, Oklahoma City, OK USA

[17] NIH, Undiagnosed Dis Program Clin Site, Bldg 10, Bethesda, MD 20892 USA

[18] Univ Washington, Seattle, WA 98195 USA

[19] Seattle Childrens Hosp, Clin Site, Seattle, WA USA

[20] Massachusetts Gen Hosp, Brigham & Womens Hosp, Harvard Affiliated Boston Childrens Hosp, Boston, MA 02114 USA

[21] Brigham Genom Med, Clin Site, Boston, MA 02114 USA

[22] Baylor Coll Med, Clin Site, Houston, TX 02115 USA

[23] Univ Utah, Clin Site, Salt Lake City, UT USA

[24] Stanford Univ, Clin Site, Stanford, CA 94305 USA

[25] Univ Miami, Clin Site, Miami, FL USA

[26] Washington Univ, Model Organism Screening Ctr, St Louis, MO 14263 USA

[27] Washington Univ, Model Organism Screening Ctr, St Louis, MO 14263 USA

[28] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[29] Univ Penn, Clin Site, Philadelphia, PA 19104 USA

[30] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA

[31] Univ Calif Vanderbilt Univ, Clin Site, Vanderbilt Univ, CA USA

[32] Univ Alabama Birmingham, Coordinating Ctr, Birmingham, AL USA

[33] Duke Univ, Clin Site, Durham, NC USA

[34] Mayo Clin Metabol Core, Rochester, MN USA

[35] Baylor Genet Sequencing Core, Houston, TX USA

[36] Harvard Med Sch, Coordinating Ctr, Boston, MA 02115 USA

[37] Columbia Univ, Clin Site, New York, NY USA

[38] Baylor Coll Med, Model Organism Screening Ctr, Houston, TX 77030 USA

[39] Univ Oregon, Model Organism Screening Ctr, Eugene, OR 97403 USA

来源：

GENETICS IN MEDICINE | 2021年 / 23卷 / 08期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

PROTEIN-KINASE-A; REGULATORY SUBUNIT; MUTATION; MICE; PKA;

D O I：

10.1038/s41436-021-01152-7

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

引用

页码：1465 / 1473

页数：9

共 31 条

[1] Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein KinaseA Subunit RI (PKA-RI) [J].