609 research outputs found
Genomic architecture and chromosome rearrangements
No full textAn increasing number of human diseases are recognized to result from recurrent DNA rearrangements involving unstable genomic regions. These are termed genomic disorders, in which the clinical phenotype is a consequence of abnormal dosage of gene(s) located within the rearranged genomic fragments. Both inter- and intrachromosomal rearrangements are facilitated by the presence of region-specific low-copy repeats (LCRs) and result from nonallelic homologous recombination (NAHR) between paralogous genomic segments. LCRs usually span approximately 10-400 kb of genomic DNA, share >or= 97% sequence identity, and provide the substrates for homologous recombination, thus predisposing the region to rearrangements
Regional assignment of the gene coding for a human Graves' disease autoantigen to 10q21.3-q22.1
No full textPatologia ereditaria da gain of function
No full textGain of function variations may lead to enhancement of existing protein function (hyper-
morph) or to acquisition of novel and possibly abnormal biological activities (neomorph).
Point mutations, chromosomal rearrangements and copy number amplifcations are common mechanisms that exert a gain of function effect in several human diseases, such as
cancer or rare developmental syndromes. Traditionally, “gain of function” and “loss of function” are considered as the antithetical functional effects of a particular genetic variation.
Accordingly, gain of function mutations may be associated with highly heterogeneous
phenotypical manifestations of the disease or even completely distinct clinical conditions
when compared to loss of function variations in the same gene. However, this dichotomic
scenario has become less cogent in the last decade with the evidence that both mutation types, when present in the same gene, may result in strikingly similar phenotypic
outcomes. Such is the paradigmatic case of TP53, which may promote tumourigenesis
after accumulation of both hypomorph and neomorph mutations. Importantly, many other
factors, such as tissue type and genetic background, may also influence the phenotype.
In the last few years, novel pathogenic mechanisms associated with gain of function
variations have emerged, including the formation of new chromatin domains, also known
as neo-TADs (Topologically Associated Domains), as a result of genomic duplications.
Importantly, many innovative personalised therapies take advantage of the specifc targeting of gain of function variations through different strategies, such as enzymatic inhibition,
RNA interference or targeted genome editing, suggesting the implementation of these
therapeutic approaches in the near futur
Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the èèq13.3 deletion syndrome
No full textThe terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses
Scotosensitive and photosensitive myoclonic seizures in an infant with trisomy 13.
No full textWe describe a male carrier of trisomy 13 with scotosensitive and photosensitive myoclonic seizures appearing at the age of 8 months and persisting until death at 20 months. The seizures consisted of massive myoclonic jerks induced both by switching the room light suddenly on or off or by IPS with a frequency of 1 s. Spontaneous seizures were absent. The child also presented from the same age with breath-holding spells. This is interesting because it represents a rare example of the co-occurrence of scotosensitive and photosensitive seizures. Furthermore, a possible association to locus on 13q31.3 has been reported for photosensitivity, while for scotosensitivity there is no previous genetic informatio
- …
