BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease affecting 1 in 8,000 newborns. The majority of patients carry bi-allelic variants in the survival of motor neuron 1 gene (SMN1). SMN1 is located in a duplicated region on chromosome 5q13 that contains Alu elements and is predisposed to genomic rearrangements. Due to the genomic complexity of the SMN region and genetic heterogeneity, approximately 50% of SMA patients remain without genetic diagnosis that is a prerequisite for genetic treatments. In this work we describe the diagnostic odyssey of one SMA patient in whom routine diagnostics identified only a maternal heterozygous SMN1Δ(7-8) deletion. METHODS: We characterized SMN transcripts, assessed SMN protein content in peripheral blood mononuclear cells (PBMC), estimated SMN genes dosage, and mapped genomic rearrangement in the SMN region. RESULTS: We identified an Alu-mediated deletion encompassing exons 2a-5 of SMN1 on the paternal allele and a complete deletion of SMN1 on the maternal allele as the cause of SMA in this patient. CONCLUSION: Alu-mediated rearrangements in SMN1 can escape routine diagnostic testing. Parallel analysis of SMN gene dosage, SMN transcripts, and total SMN protein levels in PBMC can identify genomic rearrangements and should be considered in genetically undefined SMA cases.
- Klíčová slova
- SMN1, SMN2, Alu elements, spinal muscular atrophy,
- MeSH
- delece genu * MeSH
- elementy Alu MeSH
- genetické testování metody MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- předškolní dítě MeSH
- protein přežití motorických neuronů 1 genetika metabolismus MeSH
- sekvenční analýza DNA metody MeSH
- spinální svalová atrofie diagnóza genetika MeSH
- western blotting metody MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- messenger RNA MeSH
- protein přežití motorických neuronů 1 MeSH
- SMN1 protein, human MeSH Prohlížeč
Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.
- Klíčová slova
- Cabezas syndrome, Danon disease, cullin 4B, female heterozygotes, lysosomal-associated membrane protein 2,
- MeSH
- chromozomální delece MeSH
- dospělí MeSH
- elementy Alu genetika MeSH
- exony genetika MeSH
- glykogenóza typu IIb diagnóza genetika patofyziologie MeSH
- inaktivace chromozomu X genetika MeSH
- kardiomyopatie genetika patofyziologie MeSH
- kulinové proteiny genetika MeSH
- lidé MeSH
- membránový protein 2 asociovaný s lyzozomy genetika MeSH
- mentální retardace vázaná na chromozom X genetika patofyziologie MeSH
- mutace ztráty funkce genetika MeSH
- myokard metabolismus MeSH
- sodíko-draslíková ATPasa genetika MeSH
- transkripční faktory genetika MeSH
- variabilita počtu kopií segmentů DNA genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ATP1B4 protein, human MeSH Prohlížeč
- CUL4B protein, human MeSH Prohlížeč
- kulinové proteiny MeSH
- LAMP2 protein, human MeSH Prohlížeč
- membránový protein 2 asociovaný s lyzozomy MeSH
- sodíko-draslíková ATPasa MeSH
- transkripční faktory MeSH
BACKGROUND: The origin of Western African pastoralism, represented today by the Fulani nomads, has been a highly debated issue for the past decades, and has not yet been conclusively resolved. AIM: This study focused on Alu polymorphisms in sedentary and nomadic populations across the African Sahel to investigate patterns of diversity that can complement the existing results and contribute to resolving issues concerning the origin of West African pastoralism. SUBJECTS AND METHODS: A new dataset of 21 Alu biallelic markers covering a substantial part of the African Sahel has been analysed jointly with several published North African populations. RESULTS: Interestingly, with regard to Alu variation, the relationship of Fulani pastoralists to North Africans is not as evident as was earlier revealed by studies of uniparental loci such as mtDNA and NRY. Alu insertions point rather to an affinity of Fulani pastoralists to Eastern Africans also leading a pastoral lifestyle. CONCLUSIONS: It is suggested that contemporary Fulani pastoralists might be descendants of an ancestral Eastern African population that, while crossing the Sahara in the Holocene, admixed slightly with a population of Eurasian (as evidenced by uniparental polymorphisms) ancestry. It seems that, in the Fulani pastoralists, Alu elements reflect more ancient genetic relationships than do uniparental genetic systems.
- Klíčová slova
- African Sahel, Alu insertions, Fulani nomads, Western African pastoralism,
- MeSH
- elementy Alu genetika MeSH
- lidé MeSH
- osoby s přechodným pobytem a migranti * MeSH
- polymorfismus genetický genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- subsaharská Afrika MeSH
BACKGROUND: Transposable elements form a significant proportion of eukaryotic genomes. Recently, Lexa et al. (Nucleic Acids Res 42:968-978, 2014) reported that plant long terminal repeat (LTR) retrotransposons often contain potential quadruplex sequences (PQSs) in their LTRs and experimentally confirmed their ability to adopt four-stranded DNA conformations. RESULTS: Here, we searched for PQSs in human retrotransposons and found that PQSs are specifically localized in the 3'-UTR of LINE-1 elements, in LTRs of HERV elements and are strongly accumulated in specific regions of SVA elements. Circular dichroism spectroscopy confirmed that most PQSs had adopted monomolecular or bimolecular guanine quadruplex structures. Evolutionarily young SVA elements contained more PQSs than older elements and their propensity to form quadruplex DNA was higher. Full-length L1 elements contained more PQSs than truncated elements; the highest proportion of PQSs was found inside transpositionally active L1 elements (PA2 and HS families). CONCLUSIONS: Conservation of quadruplexes at specific positions of transposable elements implies their importance in their life cycle. The increasing quadruplex presence in evolutionarily young LINE-1 and SVA families makes these elements important contributors toward present genome-wide quadruplex distribution.
- MeSH
- dlouhé rozptýlené jaderné elementy MeSH
- elementy Alu MeSH
- endogenní retroviry MeSH
- G-kvadruplexy * MeSH
- genomika MeSH
- lidé MeSH
- mapování chromozomů MeSH
- repetitivní sekvence nukleových kyselin MeSH
- transpozibilní elementy DNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- transpozibilní elementy DNA * MeSH
BACKGROUND: Mutations in the LDLR gene are the most frequent cause of Familial hypercholesterolemia, an autosomal dominant disease characterised by elevated concentrations of LDL in blood plasma. In many populations, large genomic rearrangements account for approximately 10% of mutations in the LDLR gene. METHODS: DNA diagnostics of large genomic rearrangements was based on Multiple Ligation dependent Probe Amplification (MLPA). Subsequent analyses of deletion and duplication breakpoints were performed using long-range PCR, PCR, and DNA sequencing. RESULTS: In set of 1441 unrelated FH patients, large genomic rearrangements were found in 37 probands. Eight different types of rearrangements were detected, from them 6 types were novel, not described so far. In all rearrangements, we characterized their exact extent and breakpoint sequences. CONCLUSIONS: Sequence analysis of deletion and duplication breakpoints indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved in 6 events, while a non-homologous end joining (NHEJ) is implicated in 2 rearrangements. Our study thus describes for the first time NHEJ as a mechanism involved in genomic rearrangements in the LDLR gene.
- MeSH
- elementy Alu MeSH
- genová přestavba MeSH
- hyperlipoproteinemie typ II genetika MeSH
- LDL-receptory genetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- LDL-receptory MeSH
Alus and LINEs (LINE1) are widespread classes of repeats that are very unevenly distributed in the human genome. The majority of GC-poor LINEs reside in the GC-poor isochores whereas GC-rich Alus are mostly present in GC-rich isochores. The discovery that LINES and Alus share similar target site duplication and a common AT-rich insertion site specificity raised the question as to why these two families of repeats show such a different distribution in the genome. This problem was investigated here by studying the isochore distributions of subfamilies of LINES and Alus characterized by different degrees of divergence from the consensus sequences, and of Alus, LINEs and pseudogenes located on chromosomes 21 and 22. Young Alus are more frequent in the GC-poor part of the genome than old Alus. This suggests that the gradual accumulation of Alus in GC-rich isochores has occurred because of their higher stability in compositionally matching chromosomal regions. Densities of Alus and LINEs increase and decrease, respectively, with increasing GC levels, except for the telomeric regions of the analyzed chromosomes. In addition to LINEs, processed pseudogenes are also more frequent in GC-poor isochores. Finally, the present results on Alu and LINE stability/exclusion predict significant losses of Alu DNA from the GC-poor isochores during evolution, a phenomenon apparently due to negative selection against sequences that differ from the isochore composition.
- MeSH
- dlouhé rozptýlené jaderné elementy genetika MeSH
- DNA genetika MeSH
- elementy Alu genetika MeSH
- GC bohatá sekvence genetika MeSH
- genom lidský * MeSH
- inzerční mutageneze MeSH
- lidé MeSH
- lidské chromozomy, pár 21 genetika MeSH
- lidské chromozomy, pár 22 genetika MeSH
- zastoupení bazí MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA MeSH
