Huntington disease (HD) results from polyglutamine expansion in the huntingtin protein (htt). Despite the widespread tissue expression pattern of htt, neuronal loss is highly selective to medium spiny neurons of the striatum. Huntingtin is phosphorylated on serine-421 (S421) by the pro-survival signaling protein kinase Akt (PKB) and this has been previously shown to be protective against the toxicity of polyglutamine-expanded htt in cell culture. Using an antibody specific for htt phosphorylated on S421, we now demonstrate that htt phosphorylation is present at significant levels under normal physiological conditions in human and mouse brain. Furthermore, htt phosphorylation shows a regional distribution with the highest levels in the cerebellum, less in the cortex, and least in the striatum. In cell cultures and in YAC transgenic mice, the endogenous phosphorylation of polyglutamine-expanded htt is significantly reduced relative to wild-type htt. The presence and pattern of significant htt phosphorylation in the brain indicates that this dynamic post-translational modification is important for the regulation of htt and may contribute to the selective neurodegeneration seen in HD.

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Purpose The authors report a seven-year-old male, designated FR, with severe sensorineural hearing loss. Features include round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. To investigate genetic causes for his hearing loss, genetic studies were performed. Methods History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1, GJB2, GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH). Results Results from FMR1, GJB2, GJB6, and POU3F4 sequencing and echocardiography, ECG, and abdominal ultrasound were normal. CT revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns with a widened modiolus bilaterally. CT findings are consistent with those described in persons with DFNX2 hereditary deafness. His karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25 kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene. Conclusions We hypothesize that FR's hearing loss is caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.

Nablus mask-like facial syndrome (NMLFS) has many distinctive phenotypic features, particularly tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. Over the last few years, several individuals with NMLFS have been reported to have a microdeletion of 8q21.3q22.1, demonstrated by microarray analysis. The minimal overlapping region is 93.98-96.22 Mb (hg19). Here we present clinical and microarray data from five singletons and two mother-child pairs who have heterozygous deletions significantly overlapping the region associated with NMLFS. Notably, while one mother and child were said to have mild tightening of facial skin, none of these individuals exhibited reduced facial expression or the classical facial phenotype of NMLFS. These findings indicate that deletion of the 8q21.3q22.1 region is necessary but not sufficient for development of the NMLFS. We discuss possible genetic mechanisms underlying the complex pattern of inheritance for this condition.