Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation

Abstract

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.

Figure 1

Mutations identified in the JARID1C gene in families N017 (A), L017 (B), D034 (C), P018 (D), N063 (E), D029 (F), and A034 (G). The sequence chromatograms of the index patients (asterisks) are shown beside the wild-type sequences. The corresponding pedigrees are presented above the chromatograms. Family members who have been analyzed for sequence changes are numbered. For patients with numbers in parentheses, only clinical data were available (no DNA was available for mutation analysis).

Figure 2

Northern blot analysis of poly-A⁺ RNA isolated from lymphoblastoid cell lines obtained from six patients and five controls. The blot was sequentially hybridized with a cDNA probe corresponding to nucleotides 4563–5292 of JARID1C and with a β-actin cDNA probe. Note the significant reduction of JARID1C transcript levels in patients from families N063 and P018.

Figure 3

Sequential hybridization of JARID1C (A), JARID1D (B), and β-actin (C) to a northern blot containing human poly-A⁺ RNAs from adult heart, brain, liver, pancreas, skeletal muscle, and lung. In panel A, probes correspond to nucleotides 4563–5292 of JARID1C; in panel B, probes correspond to nucleotides 4400–5128 of JARID1D; and, in panel C, probes correspond to a cDNA fragment of β-actin.

Figure 4

Schematic representation of the human JARID1C protein, showing the positions and types of mutations found. On the basis of the NCBI Conserved Domain Database, the positions of known domains and motifs are marked by different boxes, which are explained at the bottom of the figure.

Figure 5

Partial amino acid sequence alignment of the four different members of the human JARID1 family (Hs_JARID1A–Hs_JARID1D), the JARID1C orthologous protein of mouse (Mm_Jarid1c), and the homologous Lid protein of fruit fly (Dm_Lid). Amino acids that differ from the JARID1C sequence are highlighted. The four missense mutations and their positions are indicated by arrows and bold letters. The respective amino acids are identical in the six proteins.