SOBP is mutated in syndromic and nonsyndromic intellectual disability and is highly expressed in the brain limbic system

Abstract

Intellectual disability (ID) affects 1%-3% of the general population. We recently reported on a family with autosomal-recessive mental retardation with anterior maxillary protrusion and strabismus (MRAMS) syndrome. One of the reported patients with ID did not have dysmorphic features but did have temporal lobe epilepsy and psychosis. We report on the identification of a truncating mutation in the SOBP that is responsible for causing both syndromic and nonsyndromic ID in the same family. The protein encoded by the SOBP, sine oculis binding protein ortholog, is a nuclear zinc finger protein. In mice, Sobp (also known as Jxc1) is critical for patterning of the organ of Corti; one of our patients has a subclinical cochlear hearing loss but no gross cochlear abnormalities. In situ RNA expression studies in postnatal mouse brain showed strong expression in the limbic system at the time interval of active synaptogenesis. The limbic system regulates learning, memory, and affective behavior, but limbic circuitry expression of other genes mutated in ID is unusual. By comparing the protein content of the +/jc to jc/jc mice brains with the use of proteomics, we detected 24 proteins with greater than 1.5-fold differences in expression, including two interacting proteins, dynamin and pacsin1. This study shows mutated SOBP involvement in syndromic and nonsyndromic ID with psychosis in humans.

Figure 1

Gene Mapping and Mutation Identification (A) Pedigree, haplotyping, and segregation of mutation in the family. The proband is indicated by an arrow. For mutation detection by restriction analysis, amplification of a 669 bp fragment from genomic DNA was performed with the use of primers A and B. The mutation introduces a Dde1 restriction site, which digests the 669 bp fragment into 310 bp, 195 bp, and164 bp fragments. The reaction products were separated by electrophoresis on 3% NuSieve/1% agarose gels. (B) Candidate region on chromosome 6q16.3-q21, with the list of candidate genes. (C) Sequence analysis in a patient, heterozygous carrier, and control individual. M, mutant allele; C, carrier; WT, homozygous wild-type. DNA from individual IV-4 was not available for mutation segregation analysis.

Figure 2

Bioinformatics Analysis of the Genomic Conservation of the SOBP and SOBP Domain and Motif Structure (A) ECR browser analysis on human (hg18) was performed to show SOBP conservation between human and various species (danio, tetradon, fugu, Xenopus, gallus, rat, mouse, dog, rhesus, and chimp). Genomic conservation of exons (blue) and introns (orange), as well as the UTR (yellow) and repeats (green), is visualized. Layer height presents the percentage of identity (sequence conservation). Two different gene transcripts are shown at the bottom. The blue arrow shows a C>T change in nucleotide 1981 of exon 6 in SOBP. (B) Domain properties for SOBP (A7XYQ1; SOBP_HUMAN) were obtained from UniProt. Two FCS-type zinc fingers (MYM-type zinc finger with FCS sequence motif, PF06467) and two proline-rich regions (IPR000694) are shown (red and yellow, respectively). NLS localization is also presented (navy). In addition, DNA and RNA binding motifs were predicted by the RNABindR server (light blue). The results from the BindN, PPRint, and MEME servers agree with those from the RNABindR server (data not shown). The blue arrow represents residue 661, in which the reported mutation occurred, causing truncation of SOBP.

Figure 3

Mouse Sobp mRNA Is Highly Expressed in the Limbic System (A and B) In situ hybridization on coronal (A) and parasagittal (B) sections of P10 murine brains show that Sobp is expressed throughout the brain, with the strongest expression in the cortex (ctx), especially in layer V, the hippocampus (hipp), the piriform cortex (pyr ctx), the mediodorsal nucleus of the thalamus (MDn), the anterior olfactory nucleus (AON), and the mitral cell layer in the olfactory bulb (mcl). Scale bars represent 500 μm. (C) Strong Sobp expression is also observed in the amygdala (amy) and the hypothalamus (hyp). Scale bars represent 100 μm. (D) Cortical expression is strong throughout development, with the highest levels of expression in layers II/III and V and in the subplate (SP). SVZ, subventricular zone. Scale bar represents 100 μm.