TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system
Authors: Akula Shyam K. , Marciano Jack H. , Lim Youngshin , Exposito-Alonso David , Hylton Norma K. , Hwang Grace H. , Neil Jennifer E. , Dominado Nicole , Bunton-Stasyshyn Rosie K. , Song Janet H. T. , Talukdar Maya , Schmid Aloisia , Teboul Lydia , Mo Alisa , Shin Taehwan , Finander Benjamin , Beck Samantha G. , Yeh Rebecca C. , Otani Aoi , Qian Xuyu , DeGennaro Ellen M. , Alkuraya Fowzan S. , Maddirevula Sateesh , Cascino Gregory D. , Giannini Caterina ,   Undiagnosed Diseases Network, Burrage Lindsay C. , Rosenfield Jill A. , Ketkar Shamika , Clark Gary D. , Bacino Carlos , Lewis Richard A. , Segal Rosalind A. , Bazan J. Fernando , Smith Kelly A. , Golden Jeffrey A. , Cho Ginam , Walsh Christopher A. , Adams David R. , Aday Aaron , Alejandro Mercedes E. , Allard Patrick , Ashley Euan A. , Azamian Mahshid S. , Bacino Carlos A. , Baker Eva , Balasubramanyam Ashok , Barseghyan Hayk , Batzli Gabriel F. , Beggs Alan H. , Behnam Babak , Bellen Hugo J. , Bernstein Jonathan A. , Berry Gerard T. , Bican Anna , Bick David P. , Birch Camille L. , Bonner Devon , Boone Braden E. , Bostwick Bret L. , Briere Lauren C. , Brokamp Elly , Brown Donna M. , Brush Matthew , Burke Elizabeth A. , Burrage Lindsay C. , Butte Manish J. , Chen Shan , Clark Gary D. , Coakley Terra R. , Cobban Laurel A. , Cogan Joy D. , Colley Heather A. , Cooper Cynthia M. , Cope Heidi , Craigen William J. , D’Souza Precilla , Davids Mariska , Davidson Jean M. , Dayal Jyoti G. , Dell’Angelica Esteban C. , Dhar Shweta U. , Dipple Katrina M. , Dorrani Naghmeh , Dorset Daniel C. , Douglas Jessica , Douine Emilie D. , Draper David D. , Dries Annika M. , Eckstein David J. , Emrick Lisa T. , Eng Christine M. , Enns Gregory M. , Eskin Ascia , Esteves Cecilia , Estwick Tyra , Fernandez Liliana , Ferreira Carlos , Fieg Elizabeth L. , Fisher Paul G. , Fogel Brent L. , Friedman Noah D. , Gahl William A. , Godfrey Rena A. , Goldman Alica M. , Goldstein David B. , Gould Sarah E. , Gourdine Jean-Philippe F. , Groden Catherine A. , Gropman Andrea L. , Haendel Melissa , Hamid Rizwan , Hanchard Neil A. , High Frances , Holm Ingrid A. , Hom Jason , Howerton Ellen M. , Huang Yong , Jamal Fariha , Jiang Yong-hui , Johnston Jean M. , Jones Angela L. , Karaviti Lefkothea , Kelley Emily , Koeller David M. , Kohane Isaac S. , Kohler Jennefer N. , Korrick Susan , Kozuira Mary , Krasnewich Donna M. , Krier Joel B. , Kyle Jennifer E. , Lalani Seema R. , Lau C. Christopher , Lazar Jozef , LeBlanc Kimberly , Lee Brendan H. , Lee Hane , Levy Shawn E. , Lewis Richard A. , Loo Sandra K. , Loscalzo Joseph , Maas Richard L. , Macnamara Ellen F. , MacRae Calum A. , Maduro Valerie V. , Majcherska Marta M. , Malicdan May Christine V. , Mamounas Laura A. , Manolio Teri A. , Markello Thomas C. , Marom Ronit , Martin Martin G. , Martínez-Agosto Julian A. , Marwaha Shruti , May Thomas , McConkie-Rosell Allyn , McCormack Colleen E. , McCray Alexa T. , Merker Jason D. , Metz Thomas O. , Might Matthew , Mochida Ganesh , Moretti Paolo M. , Morimoto Marie , Mulvihill John J. , Murdock David R. , Murphy Jennifer L. , Muzny Donna M. , Nehrebecky Michele E. , Nelson Stan F. , Newberry J. Scott , Newman John H. , Nicholas Sarah K. , Novacic Donna , Orange Jordan S. , Orengo James P. , Pallais J. Carl , Palmer Christina GS. , Papp Jeanette C. , Parker Neil H. , Pena Loren DM. , Phillips John A. , Posey Jennifer E. , Postlethwait John H. , Potocki Lorraine , Pusey Barbara N. , Renteria Genecee , Reuter Chloe M. , Rives Lynette , Robertson Amy K. , Rodan Lance H. , Rosenfeld Jill A. , Sampson Jacinda B. , Samson Susan L. , Schoch Kelly , Scott Daryl A. , Shakachite Lisa , Sharma Prashant , Shashi Vandana , Signer Rebecca , Silverman Edwin K. , Sinsheimer Janet S. , Smith Kevin S. , Spillmann Rebecca C. , Stoler Joan M. , Stong Nicholas , Sullivan Jennifer A. , Sweetser David A. , Tan Queenie K.-G. , Tan Wen-Haan , Tifft Cynthia J. , Toro Camilo , Tran Alyssa A. , Urv Tiina K. , Vilain Eric , Vogel Tiphanie P. , Waggott Daryl M. , Wahl Colleen E. , Walker Melissa , Walley Nicole M. , Wan Jijun , Wangler Michael F. , Ward Patricia A. , Waters Katrina M. , Webb-Robertson Bobbie-Jo M. , Westerfield Monte , Wheeler Matthew T. , Wise Anastasia L. , Wolfe Lynne A. , Worthey Elizabeth A. , Yamamoto Shinya , Yang Yaping , Yang John , Yoon Amanda J. , Yu Guoyun , Zastrow Diane B. , Zhao Chunli , Zheng Allison 
Published: January 2023

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in
TMEM161B
, which encodes a multi-pass transmembrane protein of unknown function.
Tmem161b
null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b.
Tmem161b
depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the
Tmem161b
null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify
TMEM161B
as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.