The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as “AP-4 deficiency syndrome”. In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons. These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.
Summary A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general “cellular housekeeping” genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild type littermates. We found significant differences in the vocalizations of pups with the Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time, had longer pauses between vocalizations, and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech, and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme targeting pathway produce highly specific effects in mouse pup vocalizations, and establish the mouse as an attractive model for studying this disorder.
Objective. To investigate whether a human X chromosome locus of IRAK1 and MECP2 is associated with susceptibility to rheumatoid arthritis (RA), an autoimmune disease that predominantly affects women.Methods. A total of 2,334 unrelated Korean participants (including 1,318 patients with RA) were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) and 3 additional SNPs in an Xq28 region harboring MECP2 and IRAK1. Twenty-nine additional neighboring SNPs were imputed using the Korean HapMap Project data. All 37 SNPs were statistically tested for association with RA susceptibility, and 2 SNPs associated with RA were examined for their functional effects.Results. RA susceptibility was associated with multiple SNPs in a 79-kb linkage disequilibrium block harboring both MECP2 and IRAK1. The most significant association was for MECP2 SNP rs1734792 (P ؍ 0.00089), but 2 nonsynonymous IRAK1 SNPs, rs1059702 (P ؍ 0.0034) and rs1059703 (P ؍ 0.0042), which were in strong linkage disequilibrium with the MECP2 SNP (D ؍ 0.87 and 0.91, respectively) affected IRAK1 protein activity. The major haplotype of the 2 nonsynonymous SNPs was associated with a 1.7-fold increase in RA susceptibility versus the minor haplotype (P ؍ 0.0082), and with increased IRAK1 activity, which was demonstrated by a 1.7-fold increase in the intracellular activity of transcription factor NF-B.Conclusion. Our findings indicate that RA susceptibility is associated with multiple SNPs in MECP2 and IRAK1, but high linkage disequilibrium between them does not allow for further localization. Therefore, both genes remain candidates. Nevertheless, the major haplotype of the 2 nonsynonymous IRAK1 SNPs encoding for pPhe196Ser and pSer532Leu confers enhanced IRAK1 activity and, consequently, enhanced susceptibility to RA, as compared to the minor haplotype.
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