Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.
In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as "SMCX," is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.
Jensen
Lars Riff
LR
Max Planck Institute for Molecular Genetics, Berlin, Germany.
Amende
Marion
M
Gurok
Ulf
U
Moser
Bettina
B
Gimmel
Verena
V
Tzschach
Andreas
A
Janecke
Andreas R
AR
Tariverdian
Gholamali
G
Chelly
Jamel
J
Fryns
Jean-Pierre
JP
Van Esch
Hilde
H
Kleefstra
Tjitske
T
Hamel
Ben
B
Moraine
Claude
C
Gecz
Jozef
J
Turner
Gillian
G
Reinhardt
Richard
R
Kalscheuer
Vera M
VM
Ropers
Hans-Hilger
HH
Lenzner
Steffen
S
D000328:Adult; D001921:Brain / Q000254:growth & development / Q000502:physiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D018736:DNA Adducts; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked; D056466:Histone Demethylases; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010089:Oxidoreductases, N-Demethylating; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
D018736:DNA Adducts; D011506:Proteins; D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating