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Proteasome 26S, the eukaryotic proteasome, serves as the machinery for cellular protein degradation. It is composed of the 20S core particle and one or two 19S regulatory particles, composed of a base and a lid. To date, several human diseases have been associated with mutations within the 26S proteasome subunits; only one of them affects a base subunit. We now delineate an autosomal recessive syndrome of failure to thrive, severe developmental delay and intellectual disability, spastic tetraplegia with central hypotonia, chorea, hearing loss, micropenis and undescended testes, as well as mild elevation of liver enzymes. None of the affected individuals achieved verbal communication or ambulation. Ventriculomegaly was evident on MRI. Homozygosity mapping combined with exome sequencing revealed a disease‐associated p.I328T PSMC1 variant. Protein modeling demonstrated that the PSMC1 variant is located at the highly conserved putative ATP binding and hydrolysis domain, and is suggested to interrupt a hydrophobic core within the protein. Fruit flies in which we silenced the Drosophila ortholog Rpt2 specifically in the eye exhibited an apparent phenotype that was highly rescued by the human wild‐type PSMC1, yet only partly by the mutant PSMC1, proving the functional effect of the p.I328T disease‐causing variant. [ABSTRACT FROM AUTHOR]

A genome-wide homozygosity mapping and mutation analysis of consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with Pelizaeus-Merzbacher-like disease (PMLD) excluding the linkage to mutations PLP1, GJC2 and HSPD1 is presented. The findings for homozygous frameshift mutation that fully abrogates the main domain and AIMP1, encoding ARS-interacting multi-functional protein 1 demonstrated the inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.

A consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis characterized by the symptoms of visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy is reported. The findings from genome-wide linkage analysis demonstrated that the phenotype is attributed to a homozygous mutation in CA12, encoding carbonic anhydrase XII.

A study demonstrates that mutations in the SepSecS gene in the essential enzyme catalyst disrupt the sole route to the biosynthesis of selenocysteine (Sec) amino acid. The mutations are thereby seen to cause autosomal recessive progressive cerebello-cerebral atrophy (PCCA) in humans due to selenium deficiency since selenium in proteins in found in the form of Sec.

Several analyses are conducted to explain the symptoms, causes and effects of the maternally transmitted birk barel dysmorphism syndrome of mental retardation, namely hypotonia. The disorder is shown to be caused by a mutation in the genomically imprinted potassium channel KCNK9 by exhibiting a dual function of a homodimer, as well as of a heterodimer.

The brain magnetic resonance imaging technique is employed to study the causes and effects of mitochondrial complex III deficiency in humans. The homozygous mutation in UQCRQ is shown to be highly related to the deficiency.

The article highlights that lethal congenital contractural syndrome is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein.

A novel arthrogryposis phenotype lethal contractural syndrome type 3 (LCCS3) that is identical to LCCS2 except for the absence of a neurogenic bladder is described.

Individuals from two unrelated Bedouin Israeli kindreds, affected by infantile neuroaxonal dystrophy, which is an autosomal recessive progressive neurodegenerative disease are studied. Diffuse cerebellar atrophy and abnormal iron deposition in the medical and lateral globus pallidum is observed in brain imaging and progressive white-matter disease and reduction of the N-acetyl alpartate:chromium ration are evident on magnetic resonance spectroscopy, suggesting loss of mynellnation.

Author(s): Ohad S. Birk [1]; Delane E. Casiano [1]; Christopher A. Wassif [2]; Tiziana Cogliati [3]; Liping Zhao [4]; Yangu Zhao [1]; Alexander Grinberg [1]; SingPing Huang [1]; Jordan A. [...]

Abstract Background The OMIM database is a tool used daily by geneticists. Syndrome pages include a Clinical Synopsis section containing a list of known phenotypes comprising a clinical syndrome. The phenotypes are in free text and different phrases are often used to describe the same phenotype, the differences originating in spelling variations or typing errors, varying sentence structures and terminological variants. These variations hinder searching for syndromes or using the large amount of phenotypic information for research purposes. In addition, negation forms also create false positives when searching the textual description of phenotypes and induce noise in text mining applications. Description Our method allows efficient and complete search of OMIM phenotypes as well as improved data-mining of the OMIM phenome. Applying natural language processing, each phrase is tagged with additional semantic information using UMLS and MESH. Using a grammar based method, annotated phrases are clustered into groups denoting similar phenotypes. These groups of synonymous expressions enable precise search, as query terms can be matched with the many variations that appear in OMIM, while avoiding over-matching expressions that include the query term in a negative context. On the basis of these clusters, we computed pair-wise similarity among syndromes in OMIM. Using this new similarity measure, we identified 79,770 new connections between syndromes, an average of 16 new connections per syndrome. Our project is Web-based and available at http://fohs.bgu.ac.il/s2g/csiomim Conclusions The resulting enhanced search functionality provides clinicians with an efficient tool for diagnosis. This search application is also used for finding similar syndromes for the candidate gene prioritization tool S2G. The enhanced OMIM database we produced can be further used for bioinformatics purposes such as linking phenotypes and genes based on syndrome similarities and the known genes in Morbidmap.

COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole‐exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15‐mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date. [ABSTRACT FROM AUTHOR]