TY - JOUR
T1 - Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder
AU - Khalaf-Nazzal, Reham
AU - Fasham, James
AU - Inskeep, Katherine A.
AU - Blizzard, Lauren E.
AU - Leslie, Joseph S.
AU - Wakeling, Matthew N.
AU - Ubeyratna, Nishanka
AU - Mitani, Tadahiro
AU - Griffith, Jennifer L.
AU - Baker, Wisam
AU - Al-Hijawi, Fida’
AU - Keough, Karen C.
AU - Gezdirici, Alper
AU - Pena, Loren
AU - Spaeth, Christine G.
AU - Turnpenny, Peter D.
AU - Walsh, Joseph R.
AU - Ray, Randall
AU - Neilson, Amber
AU - Kouranova, Evguenia
AU - Cui, Xiaoxia
AU - Curiel, David T.
AU - Pehlivan, Davut
AU - Akdemir, Zeynep Coban
AU - Posey, Jennifer E.
AU - Lupski, James R.
AU - Dobyns, William B.
AU - Stottmann, Rolf W.
AU - Crosby, Andrew H.
AU - Baple, Emma L.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/11/3
Y1 - 2022/11/3
N2 - Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
AB - Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
KW - MARK2
KW - agyria
KW - autosomal recessive
KW - lissencephaly
KW - neurodevelopmental disorder
KW - pachygyria
KW - patronin
KW - tubulinopathy
UR - http://www.scopus.com/inward/record.url?scp=85140960390&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.09.012
DO - 10.1016/j.ajhg.2022.09.012
M3 - Article
C2 - 36283405
AN - SCOPUS:85140960390
SN - 0002-9297
VL - 109
SP - 2068
EP - 2079
JO - American journal of human genetics
JF - American journal of human genetics
IS - 11
ER -