http://llama.mshri.on.ca/publications/Irimia_Cell_2014.pdf

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.

Mutations in more than 450 different genes have been associated with intellectual disability (ID) and related cognitive disorders (CDs), such as autism. It is to be expected that this number will increase three to fourfold in the next years due to the rapid implementation of innovative high-throughput sequencing technology in genetics labs. Numerous functional relationships have been identified between the products of individual ID genes, and common molecular and cellular pathways onto which these networks converge are beginning to emerge. Prominent examples are genes involved in synaptic plasticity, Ras and Rho GTPase signaling, and epigenetic genes that encode modifiers of the chromatin structure. It thus seems that there might be common pathological patterns in ID, despite its bewildering genetic heterogeneity. These common pathways provide attractive opportunities for knowledge-based therapeutic interventions.

http://medicinaycomplejidad.org/pdf/reciente/van%20Bokhoven.%20annurev-genet%202011.pdf

Genetic and Epigenetic Networks in Intellectual Disabilities

Our understanding of endocytosis has evolved remarkably in little more than a decade. This is the result not only of advances in our knowledge of its molecular and biological workings, but also of ...

/pdf/endocytosis-and-signaling-cell-logistics-shape-the-3mbyjpcsps.pdf

Endocytosis and signaling: cell logistics shape the eukaryotic cell plan.

The purification of coated vesicles and the discovery of clathrin by Barbara Pearse in 1975 was a landmark in cell biology. Over the past 40 years, work from many labs has uncovered the molecular details of clathrin and its associated proteins, including how they assemble into a coated vesicle and how they select cargo. Unexpected connections have been found with signalling, development, neuronal transmission, infection, immunity and genetic disorders. But there are still a number of unanswered questions, including how clathrin-mediated trafficking is regulated and how the machinery evolved.

/pdf/forty-years-of-clathrin-coated-vesicles-oshnm73wta.pdf

Forty Years of Clathrin‐coated Vesicles

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.

Mutations in the Gene Encoding the Sigma 2 Subunit of the Adaptor Protein 1 Complex, AP1S2, Cause X-Linked Mental Retardation

X-Linked intellectual disability accounts for a significant fraction of males with cognitive impairment. Many of these males present with a non-syndromic phenotype and presently mutations in 17 X-linked genes are associated with these patients. Mutations in IL1RAPL1 have been found in multiple families with non-syndromic X-linked intellectual disability. All of the published mutations predict loss of function of the protein. We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism. Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations.

Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism†

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Mutations in the Gene Encoding the Sigma 2 Subunit of the Adaptor Protein 1 Complex, AP1S2, Cause X-Linked Mental Retardation

Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism†