TY - JOUR
T1 - Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities
AU - Wagner, Matias
AU - Skorobogatko, Yuliya
AU - Pode-Shakked, Ben
AU - Powell, Cynthia M.
AU - Alhaddad, Bader
AU - Seibt, Annette
AU - Barel, Ortal
AU - Heimer, Gali
AU - Hoffmann, Chen
AU - Demmer, Laurie A.
AU - Perilla-Young, Yezmin
AU - Remke, Marc
AU - Wieczorek, Dagmar
AU - Navaratnarajah, Tharsini
AU - Lichtner, Peter
AU - Klee, Dirk
AU - Shamseldin, Hanan E.
AU - Al Mutairi, Fuad
AU - Mayatepek, Ertan
AU - Strom, Tim
AU - Meitinger, Thomas
AU - Alkuraya, Fowzan S.
AU - Anikster, Yair
AU - Saltiel, Alan R.
AU - Distelmaier, Felix
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/2/6
Y1 - 2020/2/6
N2 - Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
AB - Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
KW - GARNL1
KW - RalA signaling
KW - TULIP1
KW - West syndrome
KW - epilepsy
KW - muscular hypotonia
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85078742474&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.01.002
DO - 10.1016/j.ajhg.2020.01.002
M3 - Article
C2 - 32004447
AN - SCOPUS:85078742474
SN - 0002-9297
VL - 106
SP - 246
EP - 255
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -