Gene SHANK3 mutation makes sleep disorders

Up to 80% of children with autism spectrum disorder (ASD) have sleep problems. The researching team from Washington State University found that sleep problems in patients with autism spectrum disorders may be related to mutations in the gene SHANK3, which in turn regulates the body's 24-hour day and night cycle. Their research shows that people and mice lacking of the SHANK3 gene are difficult to fall asleep.
First, the researchers analyzed sleep data from patients with Phelan-McDermid syndrome (PMS), a hereditary disease that usually occurs concurrently with autism and is thought to be associated with the SHANK3 gene. They found that patients with PMS who lacked the SHANK3 gene started at age 5 and struggled to fall asleep and wake up many times during the night.
Researchers investigated the role of SHANK3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in prefrontal cortex gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Bhlhe41, Hlf, Tef, and Nr1d1. SHANK3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall, the study shows that Shank3 is an important modulator of sleep and clock gene expression.
The researcher said: "If we can understand the molecular mechanism of sleep problems in Shank3 mutant mice, we expect this will also be closely related to sleep problems in autistic patients, which indicates a new intervention point."
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Nuclear Envelope Defects Lead to Human Diseases

In 1994, the gene that is mutated in human X-linked EmeryDreifuss muscular dystrophy was found to encode a protein of the inner nuclear envelope named emerin. This link between the nuclear envelope and human disease was only the tip of an iceberg. Now genetic defects in nuclear envelope proteins are known to cause at least 14 disorders, including muscular dystrophies, lipodystrophies, and neuropathies. The most dramatic of these is Hutchinson-Gilford progeria. Affected individuals are essentially normal at birth, but they appear to age rapidly and die in their early teens of symptoms that are typically associated with extreme age.
Over 180 mutation scattered throughout the gene encoding both lamin A and c cause over 10 different diseases, collectively termed laminopathies. At least two laminopathies are also linked to mutations in FACE-I, the membrane-associated protease that processes prelamin A. Some of the symptoms of laminopathies can be modeled in the mouse. Loss of lamin A causes disruption of the nuclear envelope and leads to a type of muscular dystrophy. Other mutations in mouse lamin A reproduce aspects of Hutchin-son-Gilford progeria.
The most surprising aspect of the laminopathies is the fact that the defects are limited to a few tissues such as striated muscle, despite the fact that lamins A/C are ubiquitous in differentiated cells throughout the body. Lamin mutations appear to compromise the stability of the nuclear envelope, so it has been suggested that muscle nuclei might be particularly sensitive to these mutations, owing to mechanical stress during contraction. However, this mechanism cannot account for the link between lamin mutations and lipodys-trophy-fat is not a force-generating tissue- neuropathy, or progeria.
An alternative suggestion is that these mutations cause disease by altering gene expression by compromising interactions between the inner nuclear membrane and chromatin. Cells from patients with Hutchinson-Gilford pro......

Proteins of the Inner Nuclear Membrane

At least a dozen, and possibly over 80, integral membrane proteins are associated with the inner nuclear membrane. Most of those that have been characterized can both anchor the lamina to the membrane and interact with chromatin. However, the function of most is unknown, though sequence analysis suggests that many might be enzymes. For example, the hydrophobic region of the lamin B receptor resembles a yeast enzyme involved in cholsterol biosynthesis and has sterol CI4 reductase activity when expressed in yeast. Well-characterized lamin-binding proteins include the lamin B receptor, emerin, and the lamina a polypeptides. Two unrelated genes-LAP1 and LAP2-produce a number of polypeptides with distinct structural and functional properties as a result of extensive alternative splicing of the primary transcripts.
These four proteins also contribute to organizing chromatin at the nuclear periphery. For example, the lamin B receptor binds heterochromatin protein HP1 and could thus link the envelope to condensed heterochromatin. The LEM domain, a degenerate 40-amino- acid motif common to LAP2, emerin, and MAN1, binds to an abundant small protein called barrier to auto integration factor (BAF) that also binds to DNA and has an important role in chromatin organization in both interphase nuclei and mitotic chromosomes. Despite their apparent roles in linking chromosomes to the nuclear envelope, live cell observations have shown that both HP1 and BAF are extremely mobile proteins.
Are these interactions between the chromosomes and the inner nuclear envelope functionally significant? This remains hotly debated, but a number of studies indicate that interactions with LAP2 and lamin A could be important in regulation of the cell cycle by the transcription factor E2F. Nuclear envelope proteins have been observed to interact with other transcriptional regulators, so alterations in gene expression might explain the link between mutations in nuclear envelope proteins and......

Structure and Assembly of the Nuclear Lamin

The nuclear lamina is a protein meshwork, typically 20 to 40 nm thick, composed of type v intermediate filament proteins called nuclear lamins are generally divided into two families. Lamin A is encoded by a gene that gives rise to four polypeptides by alternative splicing. Members of the lamin B family are the products of two distinct genes.
Lamin gene expression depends on the cell type and stage of development. All nuclei of higher eukaryotes, including early embryos, have a lamina that contains lamin B-family subunits, loss of which is lethal. Lamins A and C typically appear only later in development as cells begin to differentiate. This variation in lamina composition may affect patterns chromo-some organization, possibly contributing to different of gene expression.
Like other intermediate filament proteins, nuclear lam-ins have a central, rod-like domain that is largely a-helical. The basic building block of lamin assembly is an α-helical coiled- coil of two identical parallel polypeptides. Two large globular C-terminal domains protrude from one end. Lamin dimers self- associate end to end to form polymers. In some cases, these polymers grow as thick as 10-nmintermediate filaments.
The C-terminal globular domain contains a nuclear localization sequence that ensures the rapid import of newly synthesized lamin precursors into the nucleus through nuclear pores. Most lamin subunits acquire a hydrophobic posttranslational modification that targets them to the nuclear membrane. The modification involves the enzymatic addition of a hydrocarbon tail, a C15-isoprenoid group called farnesyl. The farnesyl group is added to a characteristic amino acid motif called the CaaX box at the carboxyl terminus of the protein. This motif was first recognized in the Ras proteins. Lamin subunits lacking a CaaX box form aggregates in the nuclear interior. Once at the nuclear membrane lamin A is processed by a specialized protease called FACE-1 that clips off t......

Structure of the Nuclear Envelope

The nuclear envelope provides a selective permeability barrier tween the nuclear compartment and the cytoplasm. This barrier ensures that only fully processed mRNAs are delivered to ribosomes for translation into protein. In addition, various chromosomal events, including DNA replication and expression of certain genes, are regulated, at least in part, by changes in the ability of factors to move from the cytoplasm into the nucleus.
The nuclear envelope is composed of two concentric lipid bilayers termed the inner and outer nuclear membranes. The outer nuclear membrane is continuous with the rough endoplasmic reticulum and shares its functions. For example, it has ribosomes attached to its outer surface. A fibrous nuclear lamina of intermediate filaments supports the inner nuclear membrane in higher eukaryotes. These and other proteins of the inner nuclear membrane mediate interactions of the envelope with chromatin. The inner and outer nuclear membranes are separated by a perinuclear space of about 30 nm that is continuous with the lumen of the endoplasmic reticulum. Nuclear pore complexes bridging both nuclear membranes provide the sole route for communication between the nucleus and cytoplasm during interphase.
Disassembly of the nuclear envelope is a critical aspect of mitosis in higher eukaryotes, as this releases the chromosomes so that they can be segregated to the daughter cells by the cytoplasmic mitotic spindle. Mitotic segregation of chromosomes to daughter cells takes place within the nucleus in some lower eukaryotes including yeasts.