Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment.
Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.|Department of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, H3A 1A4, Canada.
Myriam
M
Srour
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.
Véronique
V
Caron
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, 10029.
Toni
T
Pearson
Verona Pediatrics, Verona, New Jersey, 07044.
Sarah B
SB
Nielsen
Division of Medical Genetics, Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, J1H 5N4, Canada.
Sébastien
S
Lévesque
Department of Pediatrics, Université de Montréal, Montreal, H3T 1J4, Canada.
Marie-Ange
MA
Delrue
Division of Genetics and Metabolism, All Children's Hospital, St-Petersburg, Florida 33701.
Troy A
TA
Becker
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.
Fadi F
FF
Hamdan
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.|Department of Neurosciences, Université de Montréal, Montreal, H3T 1J4, Canada.
Zoha
Z
Kibar
Carle Physician Group, Urbana, Illinois, 61802.
Shannon G
SG
Sattler
Carle Physician Group, Urbana, Illinois, 61802.
Michael C
MC
Schneider
Génétique Médicale, Hôpital Jean Verdier AP-HP, C.H.U. Paris Nord, Bondy, 93140, France.
Pierre
P
Bitoun
Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, Toulouse, 31059, France.|Université Paul-Sabatier, Toulouse III, EA-4555 and Inserm U1056, Toulouse, 31000, France.
Nicolas
N
Chassaing
Baylor College of Medicine, Houston, Texas, 77030.
Jill A
JA
Rosenfeld
Baylor College of Medicine, Houston, Texas, 77030.
Fan
F
Xia
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, 21205.
Sonal
S
Desai
Children's Hospital of San Antonio San Antonio, Texas, 78207.
Elizabeth
E
Roeder
Division of Genetics and Genomic Medicine, Univerity of California-Irvine Medical Center, Orange, California, 92868.
Virginia
V
Kimonis
Division of Genetics and Genomic Medicine, Univerity of California-Irvine Medical Center, Orange, California, 92868.
Adele
A
Schneider
Children's Hospital of San Antonio San Antonio, Texas, 78207.
Rebecca Okashah
RO
Littlejohn
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, M13 9WL, UK.
Sofia
S
Douzgou
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.|Department of Obstetrics and Gynecology, Université de Montréal, Montreal, H3T 1J4, Canada.|Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, H3T 1J4, Canada.
André
A
Tremblay
CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.|Department of Pediatrics, Université de Montréal, Montreal, H3T 1J4, Canada.|Department of Neurosciences, Université de Montréal, Montreal, H3T 1J4, Canada.|Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, H3T 1J4, Canada.
Jacques L
JL
Michaud
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D020821:Dystonic Disorders; D005260:Female; D000073659:Gain of Function Mutation; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009069:Movement Disorders / Q000235:genetics*; D020125:Mutation, Missense; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics*; D015533:Transcriptional Activation
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta
RARB; developmental delay; gain-of-function; intellectual disability; movement disorder; retinoic acid