TY - JOUR
T1 - Identification and characterization of two novel JARID1C mutations
T2 - Suggestion of an emerging genotype-phenotype correlation
AU - Rujirabanjerd, Sinitdhorn
AU - Nelson, John
AU - Tarpey, Patrick S.
AU - Hackett, Anna
AU - Edkins, Sarah
AU - Raymond, F. Lucy
AU - Schwartz, Charles E.
AU - Turner, Gillian
AU - Iwase, Shigeki
AU - Shi, Yang
AU - Futreal, P. Andrew
AU - Stratton, Michael R.
AU - Gecz, Jozef
PY - 2010/3
Y1 - 2010/3
N2 - Mental retardation (MR) is characterized by cognitive impairment with an IQ 70. Many of the major causes are genetically determined and the 30% male excess suggests that mutations in genes carried on the X chromosome are disproportionably represented. One such gene, jumonji AT-rich interactive domain 1C (JARID1C) on Xp11.2, has been identified in families with X-linked MR (XLMR), with 18 different mutations reported to date. As part of a systematic resequencing of 720 genes in 208 XLMR families of the International Genetic of Learning Disability (IGOLD) consortium, two novel nucleotide changes in the JARID1C coding region were identified, with the nucleotide changes segregating with the disease phenotype in the two families. The first mutation is a single-nucleotide insertion in exon 21 (c.3258-3259insC p.K1087fs 43) causing a frameshift and resulting in a premature termination codon (PTC). Such PTC-containing mRNAs are generally degraded by nonsense-mediated mRNA decay (NMD) surveillance, but our results show that this is not the case with this mutation. The other change is a single-nucleotide substitution in exon 12 (c.1160C>A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P544T). Functional analysis shows that this amino-acid substitution compromises both tri-and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families.
AB - Mental retardation (MR) is characterized by cognitive impairment with an IQ 70. Many of the major causes are genetically determined and the 30% male excess suggests that mutations in genes carried on the X chromosome are disproportionably represented. One such gene, jumonji AT-rich interactive domain 1C (JARID1C) on Xp11.2, has been identified in families with X-linked MR (XLMR), with 18 different mutations reported to date. As part of a systematic resequencing of 720 genes in 208 XLMR families of the International Genetic of Learning Disability (IGOLD) consortium, two novel nucleotide changes in the JARID1C coding region were identified, with the nucleotide changes segregating with the disease phenotype in the two families. The first mutation is a single-nucleotide insertion in exon 21 (c.3258-3259insC p.K1087fs 43) causing a frameshift and resulting in a premature termination codon (PTC). Such PTC-containing mRNAs are generally degraded by nonsense-mediated mRNA decay (NMD) surveillance, but our results show that this is not the case with this mutation. The other change is a single-nucleotide substitution in exon 12 (c.1160C>A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P544T). Functional analysis shows that this amino-acid substitution compromises both tri-and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families.
KW - JARID1C
KW - JmjC domain
KW - Mutation analysis
KW - X-linked mental retardation
UR - http://www.scopus.com/inward/record.url?scp=77149178699&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2009.175
DO - 10.1038/ejhg.2009.175
M3 - Article
C2 - 19826449
AN - SCOPUS:77149178699
SN - 1018-4813
VL - 18
SP - 330
EP - 335
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -