A novel mutation in JARID1C gene associated with mental retardation

Santos, Cristina; Rodríguez‐Revenga, Laia; Madrigal, Irene; Badenas, Cèlia; Pineda, Merçè; Milá, Montserrat

doi:10.1038/sj.ejhg.5201608

Cited by 73 publications

(64 citation statements)

References 11 publications

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“…Currently, there are 20 mutations, including the two reported in this study, in 52 affected males ( Figure 5, Table 2). 2,[6][7][8][9] Some carrier females, with generally mild intellectual disability, have also been reported. These include three carrier females from the K8545 family of Abidi et al, 6 one carrier female from the family N063 of Jensen et al, 2 one from family A015 of Tzschach et al, 9 and one from Family 1 and two from Family 2 (see above) reported here.…”

Section: Jarid1c Mutations and Their Phenotypesmentioning

confidence: 99%

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Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

et al. 2009

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Mental retardation (MR) is characterized by cognitive impairment with an IQ o70. Many of the major causes are genetically determined and the B30% 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.1160C4A) 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.

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Section: Jarid1c Mutations and Their Phenotypesmentioning

confidence: 99%

“…4,5 Mutations in the JARID1C gene have been reported in patients with X-linked mental retardation (XLMR). 2,[6][7][8][9] Eighteen mutations in JARID1C have been reported to date and are spread throughout the gene. Affected individuals with JARID1C mutations show a mild-tosevere range of intellectual disability.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

et al. 2009

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“…Patients carrying one of the well characterized X-linked mental retardation mutations in SMCX (S451R) developed mental retardation and also showed mild deformities in the tongue and fingers (36). However, the molecular consequence(s) of this mutation was not known.…”

Section: T359r a Substitution Mutation Corresponding To A Human Smcxmentioning

confidence: 99%

“…tations in SMCX (JARID1C), a human homolog of Jhd2, have been associated with X-linked mental retardation (35)(36)(37). Patients carrying one of the well characterized X-linked mental retardation mutations in SMCX (S451R) developed mental retardation and also showed mild deformities in the tongue and fingers (36).…”

Section: T359r a Substitution Mutation Corresponding To A Human Smcxmentioning

confidence: 99%

The JmjN Domain of Jhd2 Is Important for Its Protein Stability, and the Plant Homeodomain (PHD) Finger Mediates Its Chromatin Association Independent of H3K4 Methylation

Huang

Chandrasekharan

Chen

et al. 2010

Journal of Biological Chemistry

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Histone lysine methylation is a dynamic process that plays an important role in regulating chromatin structure and gene expression. Recent studies have identified Jhd2, a JmjC domaincontaining protein, as an H3K4-specific demethylase in budding yeast. However, important questions regarding the regulation and functions of Jhd2 remain unanswered. In this study, we show that Jhd2 has intrinsic activity to remove all three states of H3K4 methylation in vivo and can dynamically associate with chromatin to modulate H3K4 methylation levels on both active and repressed genes and at the telomeric regions. We found that the plant homeodomain (PHD) finger of Jhd2 is important for its chromatin association in vivo. However, this association is not dependent on H3K4 methylation and the H3 N-terminal tail, suggesting the presence of an alternative mechanism by which Jhd2 binds nucleosomes. We also provide evidence that the JmjN domain and its interaction with the JmjC catalytic domain are important for Jhd2 function and that Not4 (an E3 ligase) monitors the structural integrity of this interdomain interaction to maintain the overall protein levels of Jhd2. We show that the S451R mutation in human SMCX (a homolog of Jhd2), which has been linked to mental retardation, and the homologous T359R mutation in Jhd2 affect the protein stability of both of these proteins. Therefore, our findings provide a mechanistic explanation for the observed defects in patients harboring this SMCX mutant and suggest the presence of a conserved pathway involving Not4 that modulates the protein stability of both yeast Jhd2 and human SMCX.

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“…In contrast, only two autosomal genes have been shown to cause autosomal recessive NSMR [12]. However, more than 50% of individuals with MR remain undiagnosed [13]. One gene locus for NSMR was identified in an Israeli Arab village, where the carrier frequency was found to be 1 in 11 newborns [14].…”

Section: Introductionmentioning

confidence: 99%

Mental retardation and consanguinity in a selected region of the Israeli Arab community

Sharkia¹,

Azem

Kaiyal

et al. 2010

Open Medicine

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AbstractThe prevalence of genetic diseases and congenital malformation in the Israeli Arab community is relatively high, but its distribution is not uniform. The aim of this study was to estimate the frequency of mental retardation disorders in children living in 5 Israeli Arab villages and determine its association with consanguinity. Mental retardation was found to affect 300 children in the screened population, yielding an overall prevalence of 14.5 per 1000. Most of those affected (68%) were the offspring of consanguineous marriages. One village with a high prevalence (4.3%) of neurological hereditary diseases was studied in detail. The prevalence of neurological hereditary diseases and mental retardation associated with consanguinity in these children highlights the need to implement appropriate preventive program.

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A novel mutation in JARID1C gene associated with mental retardation

Cited by 73 publications

References 11 publications

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype–phenotype correlation

The JmjN Domain of Jhd2 Is Important for Its Protein Stability, and the Plant Homeodomain (PHD) Finger Mediates Its Chromatin Association Independent of H3K4 Methylation

Mental retardation and consanguinity in a selected region of the Israeli Arab community

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