BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs). The founder mutation also predisposes heterozygous carriers to cancer, apparently however, with a higher risk in the Czech Republic/Slovakia (CS) than in Poland. AIM: To examine whether the age of cancer manifestation and cancer death of NBN homozygotes is different between probands from CS and Poland. METHODS: The study is restricted to probands born until 1989, before replacement of the communist regime by a democratic system in CS and Poland, and a substantial transition of the health care systems. Moreover, all patients were recruited without knowledge of their genetic status since the NBN gene was not identified until 1998. RESULTS: Here, we show that cancer manifestation of NBN homozygotes is at a significantly earlier age in probands from CS than from Poland. This is explained by the difference in natural and medical radiation exposure, though within the permissible dosage. CONCLUSION: It is reasonable to assume that this finding also sheds light on the higher cancer risk of NBN heterozygotes in CS than in Poland. This has implications for genetic counseling and individualized medicine also of probands with other DNA repair defects.
BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.
- MeSH
- dítě MeSH
- heterozygot MeSH
- homeostáza telomer genetika MeSH
- homozygot MeSH
- jaderné proteiny genetika MeSH
- karyotypizace MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- modely nemocí na zvířatech MeSH
- myši transgenní MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- předškolní dítě MeSH
- progerie genetika patologie MeSH
- proteiny buněčného cyklu genetika MeSH
- syndrom Nijmegen breakage komplikace genetika patologie MeSH
- telomerasa metabolismus MeSH
- telomery patologie MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
- MeSH
- detekce genetických nosičů MeSH
- dospělí MeSH
- efekt zakladatele * MeSH
- haplotypy MeSH
- jaderné proteiny genetika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- oprava DNA MeSH
- poškození DNA MeSH
- proteiny buněčného cyklu genetika MeSH
- rozmnožování genetika MeSH
- syndrom Nijmegen breakage etnologie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
- MeSH
- dítě MeSH
- ledviny * abnormality MeSH
- lidé MeSH
- močové ústrojí abnormality MeSH
- obstrukce močovodu * diagnóza patologie terapie MeSH
- ureter patologie MeSH
- ureterokéla diagnóza terapie MeSH
- vrozené vady * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.
- MeSH
- alely MeSH
- dítě MeSH
- dospělí MeSH
- exom MeSH
- faciální stigmatizace MeSH
- fenotyp MeSH
- genetické asociační studie * MeSH
- genotyp MeSH
- interakční proteinové domény a motivy genetika MeSH
- konformace proteinů MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- molekulární modely MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- Noonanové syndrom diagnóza genetika MeSH
- proteiny sevenless chemie genetika MeSH
- substituce aminokyselin MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.
- MeSH
- cilie metabolismus MeSH
- cytoplazmatické dyneiny chemie genetika MeSH
- exom genetika MeSH
- fibroblasty metabolismus MeSH
- fluorescenční protilátková technika MeSH
- heterozygot MeSH
- lidé MeSH
- mutace genetika MeSH
- nesmyslný kodon genetika MeSH
- sekvenční analýza DNA MeSH
- terciární struktura proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.
- MeSH
- adaptorový proteinový komplex 4 genetika MeSH
- dítě MeSH
- kvadruplegie diagnóza genetika MeSH
- lidé MeSH
- mentální retardace diagnóza genetika MeSH
- mladiství MeSH
- posunová mutace * MeSH
- sourozenci MeSH
- syndrom MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We identified a de novo deletion of 14q11.2 in a Czech patient with developmental delay, mild autistic features, macrosomy, macrocephaly, orthognathic deformities, and dysmorphic facial features. The clinical follow-up of the patient lasting 14 years documented changes in the facial dysmorphism from infancy to adolescence. The deletion affects approximately 200 kb of DNA with five protein-coding genes and two snoRNA genes. Two of the protein-coding genes, SUPT16H and CHD8, have been proposed as candidate genes for a new microdeletion syndrome. Our patient further supports the existence of this syndrome and extends its phenotypic spectrum, especially points to the possibility that orthognathic deformities may be associated with microdeletions of 14q11.2. CHD8 mutations have been found in patients with neurodevelopmental disorders and macrocephaly. The HNRNPC gene, repeatedly deleted in patients with developmental delay, is another candidate as its 5́ end is adjacent to the deletion, and the expression of this gene may be affected by position effect.
- MeSH
- chromozomální delece * MeSH
- DNA vazebné proteiny genetika MeSH
- lidé MeSH
- lidské chromozomy, pár 14 genetika MeSH
- megalencefalie diagnóza genetika MeSH
- mentální retardace diagnóza genetika MeSH
- mladiství MeSH
- mnohočetné abnormality diagnóza genetika MeSH
- následné studie MeSH
- transkripční faktory genetika MeSH
- vývojové poruchy u dětí diagnóza genetika MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Východisko. Zvýšená pravděpodobnost vzniku chromozomálních aberací u plodů matek starších 35 let je obecně známa a již 40 let je indikací k vyšetření karyotypu plodu při invazivní metodě prenatální diagnostiky, neboť genetické riziko a jeho klinický význam je podstatně vyšší než riziko spojené s nezbytnou amniocentézou. Mutagenní vliv vyššího věku otců je znám jen genetikům (1–4). Důvodem je nepochybně řádově nižší riziko vzniku čerstvých genových mutací, velké spektrum možných mutovaných genů a jen limitovaný počet autozomálně dominantně determinovaných poruch s bezprostřední manifestací po porodu. Abiotrofický charakter některých afekcí umožňuje jen omezenou nabídku jejich prevence neinvazivními metodami prenatální diagnostiky. Metody. V souboru 83 pacientů s autozomálně dominantně dědičnými syndromy spektra neurokardiofaciokutánní symptomatiky (NCFCs) jsme zhodnotili genealogická data a věk rodičů, abychom ověřili podíl tohoto mutagenního faktoru na restituci populační incidence při vysokém selekčním koeficientu (0,65). Syndrom neurokardiofaciokutánního spektra (5–7) byl zvolen po identifikaci odpovědných genů, aby mohla být na molekulární úrovni ověřena diagnóza pacientů a rozlišeny formy zděděné a mutace vzniklé de novo. Závěr. V souboru 83 pacientů s klinickou diagnózou NCFC syndromu byla u 32 detekována mutace v PTPN11 genu, u deseti mutace v SOS1 genu, u čtyř mutace v HRAS genu, u tří pacientů mutace v RAF1 genu, u dvou pacientů mutace v BRAF genu a mutace v MEK1, KRAS a NRAS genech detekována vždy u jednoho pacienta. Mutace de novo byla zjištěna u 35 pacientů a u 19 pacientů byla mutace děděna. Selekční koeficient 0,60 (29 de novo ze 48 ) byl zjištěn u pacientů s Noonanovým a LEOPARD syndromy (mutace v PTPN11, SOS1 a RAF1, KRAS a NRAS genech), syndromy Costello a kardiofaciokutánní byly ve všech šesti případech důsledkem čerstvé mutace v HRAS a BRAF genech. U 29 pacientů nemohla být diagnóza NCFC syndromu potvrzena, mutace nebyla v žádném z osmi genů detekována.
Background. Increased frequency of chromosomal aberration in children of mothers aged 35 years and older is very well known and since 1973 it is an indication to investigate the foetal karyotype in cells obtained by invasive method (amniocentesis), because the genetic risk of severe affection is higher than the risk of necessary invasive method. Mutagenic effect of advanced paternal age is known only among geneticists (1–4). The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last not least the limited spectrum of autosomal dominant disorders without abiotrofic character. Therefore the preventive methods for elimination of this risk are very limited. Only a few of them could be recognized prenatally by noninvasive methods of prenatal diagnostics. Methods. Genealogical, anamnestic and clinical data of 83 patients were studied with clinical suspection on neurocardiofaciocutaneous syndrome (NCFCs) (5–7). The diagnosis has not been confirmed in 29 patients, no mutation was detected in 8 investigated genes (PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS, NRAS). In 54 patients with autosomal dominant inherited Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome the diagnosis was confirmed on DNA level and the biological fitness was estimated for each disorder. Paternal age at conception was compared in the group of patients with familial and sporadic occurrence of Noonan and NCFC syndromes. The clinical prognosis of this disorder is represented by biological fitness of patients. Coefficient of selection is 0,6 in Noonan and LEOPARD syndromes (29 from 48). All 6 patients with Costello and cardiofaciocutaneous syndromes developed due to a new mutation. Conclusion. Paternal age at birth was studied in 83 children patients with autosomal dominant Neurocardiofaciocutaneous syndrome (Noonan, LEOPARD, Costello, CFC) with a high population incidence and decreased biological fitness. Due to severe congenital heart defects, failure to thrive in infancy, increased risk for malignancy and further health problems the clinical prognosis of patients in the past was not good. Therefore high mutation rate is expected until now. Identification of genes responsible for manifestation of this disorder, enables to confirm the diagnosis and to recognize inherited and de novo mutations. Genealogy and DNA analysis of PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS and NRAS were obtained in cohort of 54 patients with NCFC syndromes and their parents. There were 48 patients with Noonan and LEOPARD syndromes, in 29 cases due to mutation de novo, 19 patients inherited the mutation from one of parents. All 6 patients with Costello syndrome and CFC syndrome were affected due to new mutation. DNA analysis revealed 32 mutations in PTPN11 gene, mutation in SOS1 gene was found in 10 patients, RAF1 mutation was present in 3 patients; mutation in MEK1, KRAS and NRAS genes was present in one patient each. In Costello syndrome and CFC syndrome mutations in HRAS (4 patients) and BRAF (2 patients) genes were detected. Genealogic data allow analysing parental age in the group of patients with new mutation and inherited mutation. Paternal age at conception of patients with Noonan syndrome due to new mutation was significantly increased in comparison to the group of fathers of Noonan patients with inherited mutation – 38,4 years and 29,6 years, resp., range 28 to 55 years and 25 to 35 years, resp. Maternal age was slightly increased too, –30,9 and 27,7, resp. and range 24 to 42 years and 21 to 36 years, resp. but not significantly. The results support the mutagenic effect of paternal age, espec. autosomal dominant mutations.
- MeSH
- chromozomální aberace MeSH
- EDTA MeSH
- kraniofaciální abnormality * etiologie MeSH
- lidé MeSH
- mutace * genetika MeSH
- mutační analýza DNA MeSH
- mutageneze * MeSH
- neurofibromin 1 genetika MeSH
- Noonanové syndrom diagnóza genetika MeSH
- otcové MeSH
- porod MeSH
- prenatální diagnóza MeSH
- rodiče MeSH
- sekvenční analýza MeSH
- syndrom Noonanové s mnohočetnými pihami diagnóza genetika MeSH
- věk otce * MeSH
- věkové faktory * MeSH
- Check Tag
- lidé MeSH
