Rate Of New Mutations Research Articles

Genes of Chernobyl children

Transgenerational effects have long been expected in children from parents exposed to radiation from atomic bombs in Japan in 1945 or from the Chernobyl disaster in 1986. These effects have in fact proven hard to detect. A new large-scale study based on high-quality whole genome sequencing of father/mother/child trios in which the parental radiation dose is known now demonstrates that the rate of new mutations (50/70 per generation) is not detectably increased when comparing irradiated and non-irradiated parents. This solid data shows conclusively that transgenerational effects of irradiation from the Chernobyl disaster are absent or undetectable.

Diffuse neurofibroma of the chest and abdominal wall invading the diaphragm leads to diaphragmatic eventration: case report

BackgroundNeurofibromatosis type 1 (NF1) is an autosomal dominant condition with a high rate of new mutation and variable expression. Diffuse neurofibroma of the epidermis invading deeper organs is rare.We report a case of diffuse subcutaneous neurofibroma in the thoracoabdominal wall which had invaded the diaphragm and caused diaphragmatic eventration.Case presentationWe describe a patient with diffuse neurofibroma of the chest and abdomen who was admitted to the hospital due to sudden abdominal pain and a possible diaphragmatic hernia. We performed thoracotomy and found that the neurofibroma had invaded the diaphragm and caused diaphragmatic eventration.ConclusionsThis occurrence has not been reported, and it shows that although neurofibromatosis is a benign disease, it still has the biological behavior of a malignant tumor and may cause a serious impact on and damage to other organs.

Mycobacterium tuberculosis progresses through two phases of latent infection in humans

Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.

Kognitivni fenotip kod neurofibromatoze tip 1

Neurofibromatoses are a set of different genetic disorders that have a common characteristic of the appearance of nervous system tumors. There are three forms of the disease, of which type 1 neurofibromatosis (NF 1) is the most common. NF 1 is an inherited autosomal-dominant disease, with a high rate of new mutations. In addition to the many physical manifestations and complications that occur in persons with NF 1, there are also numerous cognitive difficulties, including lower general intellectual functioning, learning difficulties, but also problems in attention, visual abilities, executive functions, and speech. Attention disorders are up to three times more common in people with NF 1, while learning disabilities are present in more than half of these subjects. Disturbances in the field of visuospatial perception are recognisable even in the preschool period. About 80% of children with NF1 exhibit various speech and language disorders: slow early speech development, slower vocabulary enrichment, syntactic, semantic and phonological speech disorders. Disruption of executive functions will manifest itself in the areas of working memory, organisation, planning / problem solving. This will reflect as the underperformance in academic achievement. Nearly one-third of these persons have emotional and social problems.

Parental age and risk of genetic syndromes predisposing to nervous system tumors: nested case-control study.

PurposePhacomatoses are genetic syndromes that are associated with increased risk of developing nervous system tumors. Phacomatoses are usually inherited, but many develop de novo, with unknown etiology. In this population-based study, we investigated the effect of parental age on the risk of phacomatoses in offspring.Patients and methodsThe study was a population-based nested case–control study. All individuals born and residing in Sweden between January 1960 and December 2010 were eligible for inclusion. Using the Patient Register, 4625 phacomatosis cases were identified and further classified as familial or nonfamilial. Ten matched controls per case were randomly selected from the eligible population. Data were analyzed using conditional logistic regression. Analyses were conducted for neurofibromatosis alone (n=2089) and other phacomatoses combined (n=2536).ResultsCompared with offspring of fathers aged 25–29 years, increased risk estimates of nonfamilial neurofibromatosis were found for offspring of fathers aged 35–39 years (odds ratio [OR]=1.43 [95% CI 1.16–1.74]) and ≥40 years (OR =1.74 [95% CI 1.38–2.19]). For other nonfamilial phacomatoses, the risk estimate for offspring of fathers aged ≥40 years was OR =1.23 (95% CI 1.01–1.50). Paternal age was not associated with familial phacomatoses, and no consistent association was observed with maternal age.ConclusionThe findings show a consistent increase in risk of de novo occurrence of phacomatoses predisposing to nervous system tumors in offspring with increasing paternal age, most pronounced for neurofibromatosis, while maternal age did not seem to influence the risk. These findings suggest an increasing rate of new mutations in the NF1 and NF2 genes in spermatozoa of older fathers.

The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population.

Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.

Fluctuating Selection in the Moran.

Contrary to classical population genetics theory, experiments demonstrate that fluctuating selection can protect a haploid polymorphism in the absence of frequency dependent effects on fitness. Using forward simulations with the Moran model, we confirm our analytical results showing that a fluctuating selection regime, with a mean selection coefficient of zero, promotes polymorphism. We find that increases in heterozygosity over neutral expectations are especially pronounced when fluctuations are rapid, mutation is weak, the population size is large, and the variance in selection is big. Lowering the frequency of fluctuations makes selection more directional, and so heterozygosity declines. We also show that fluctuating selection raises dn/ds ratios for polymorphism, not only by sweeping selected alleles into the population, but also by purging the neutral variants of selected alleles as they undergo repeated bottlenecks. Our analysis shows that randomly fluctuating selection increases the rate of evolution by increasing the probability of fixation. The impact is especially noticeable when the selection is strong and mutation is weak. Simulations show the increase in the rate of evolution declines as the rate of new mutations entering the population increases, an effect attributable to clonal interference. Intriguingly, fluctuating selection increases the dn/ds ratios for divergence more than for polymorphism, a pattern commonly seen in comparative genomics. Our model, which extends the classical neutral model of molecular evolution by incorporating random fluctuations in selection, accommodates a wide variety of observations, both neutral and selected, with economy.

A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition caused by dominant loss-of-function mutations of the tumor suppressor gene NF1 that encodes neurofibromin, a negative regulator of RAS activity. Mutation analysis of NF1 located at 17q11.2 has been hampered by the large size of the gene, the high rate of new mutations, the lack of mutational clustering, and the presence of several homologous loci. To date, about 80% of the reported NF1 mutations are predicted to result in protein truncation, but very few studies have correlated the causative NF1 mutation with its effect at the protein level. We evaluated a novel diagnostic method to detect truncated forms of neurofibromin in a large cohort of unrelated subjects suspected of having NF1, according to the NIH consensus criteria. Western blot analysis was carried out on protein extracts from patients' leukocytes to highlight the possible presence of altered neurofibromin as a result of mutations in NF1. Truncated neurofibromin was identified in 274/336 patients (81%), confirming the usefulness and reproducibility of the proposed diagnostic approach. Our methodology can be routinely applied in the diagnostic setting, thanks to its simplicity and reliability. Combined with molecular approaches, it may increase the accuracy and efficiency of NF1 genetic testing. We evaluated a novel diagnostic method to detect truncated forms of neurofibromin in patients fulfilling the clinical criteria for Neurofibromatosis 1. Western blot analysis identified truncated neurofibromin in 274/336 patients (81%). Our results indicate that the proposed technique is cheap and reliable, and could ideally be performed as a preliminary biochemical screening before molecular analysis of the NF1 gene.

Manifestations anxieuses dans la neurofibromatose type 1 : à propos d’un cas

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is one of the most frequent human genetic diseases, with a prevalence of one case in 3000 births, an autosomal dominant mode of inheritance, and a high rate of new mutations. NF1 has markedly variable clinical expression, with manifestations ranging from mild lesions to several complications and functional impairment. The complications are age-specific. Psychiatric disorders are more frequent in NF1 than in the general population, especially in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. This report is based on a clinical case and discusses the relationship between neurofibromatosis type 1 and psychiatric disorders, particularly anxiety disorders. This case concerns a 13-year-old girl, the first child of healthy and non-consanguineous parents. The patient's history showed normal psychomotor and psychoaffective development. Her father and paternal grandmother had isolated café-au-lait spots. In June 2013, a subcutaneous mass appeared in her right thigh. She consulted a neurologist and was explored. The physical examination revealed signs of NF1. She had café-au-lait spots on the trunk and extremities, and a neurofibroma in the right thigh. Bilateral ophthalmic examination revealed multiple Lish nodules. After 1 month, a psychiatric consultation was requested for sad mood and night terrors. Obsessive compulsive disorder and generalized anxiety disorder were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The current psychiatric literature does not provide full explanations of anxiety symptoms associated with NF1. Some authors have tried to explain the link between NF1 and psychiatric disorders, and several etiopathogenic hypotheses have been discussed. In our case, a concomitant diagnosis of NF1 and anxiety disorders was made at the age of 13. However, anxiety symptoms started to appear before age 4; they increased gradually and occupied the foreground. This would strengthen the hypothesis of genetic determinism in NF1 patients. The question that arises is: is it a fortuitous association of psychiatric disorders and NF1 or are they psychiatric manifestations induced by a multisystem disease? More detailed investigations are necessary to clarify the etiopathogenic and psychopathological mechanisms that would cause psychiatric comorbidity associated with NF1.

Late Onset of Multiple Basal Cell Carcinomas in a Patient with Gorlin-Goltz Syndrome Previously Treated for Hodgkin’s Lymphoma/ Kasna pojava multiplog bazocelularnog karcinoma kod pacijenta sa Gorlin-Golcovim sindromom prethodno lečenog od Hočkinovog limfoma

Abstract Development of multiple basal cell carcinomas is commonly associated with immunosuppression or genetic disorders. The latter include congenital diseases such as Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome. It is an autosomal dominant inherited disorder characterized by the development of multiple basal cell carcinomas at an early age and a variable combination of other phenotypic abnormalities that result in multiple organ involvement. The susceptibility gene was mapped to chromosome 9q22.3-3.1. Like other tumor suppressor genes, PTCH1 gene shows frequent deletion and a whole variety of other mutations. A high rate of new mutations and the variable expressivity of the condition make full diagnostic assessment difficult, especially in mildly affected individuals with no family history of the condition. It has been postulated that the presence of two major features or one major feature with two minor features classify a condition as Gorlin-Goltz syndrome. We present a 42-year-old male patient with a 6-year-long history of multiple smooth and/or rough skin patches and plaques on the back and shoulders. Some of the lesions gradually progressed and increased in number without any sensation. Dotlike, flesh-colored and brownish pits were found on the patient’s palms. Further investigations revealed many musculoskeletal and craniofacial congenital abnormalities such as pectus excavatum, frontal and parietal bossing, exotropia, ectopic teeth (impacted tooth), mandibular hyperplasia, broad nose. Histopathological examination by light microscopy of biopsies taken from the nodular and patchy skin lesions showed findings typical for basal cell carcinoma. Family history revealed no members with similar health disorders. The patient was treated for Hodgkin’s lymphoma with chemotherapy and radiation therapy 20 years before, with good therapeutic results, and no additional treatment was administered in the last ten years. The treatment for multiple basal cell carcinomas included: 5% imiquimod cream, 5 days a week, for 12 weeks. After 12 weeks of treatment, the nodular lesion and all the superficial lesions cleared. One month later the lesions disappeared completely without any residual signs. The patient was advised to use adequate photoprotection and to avoid future uncontrolled sun exposure. On follow-up visits during a three year period, no recurrent or new lesions indicative for BCC were seen. This is a case with late-onset multiple BCC in a patient with Gorlin-Goltz syndrome and a history of prior Hodgkin’s lymphoma. To the best of our knowledge hitherto only two cases of Hodgkin’s lymphoma in patients with Gorlin-Goltz syndrome have been reported in the literature. We also present therapeutic results of topical imiquimod for multiple basal cell carcinomas with no recurrent lesions over a three-year follow-up.

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4–6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4–6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends

BackgroundNeurofibromatosis Type 1(NF-1) has autosomal dominant inheritance with complete penetrance, variable expression and a high rate of new mutation. Pheochromocytoma occurs in 0.1%-5.7% of patients with NF-1.Case presentationWe present the case of a 37-year-old patient with laparoscopically resected pheochromocytoma. He was investigated for hypertension, flushing and ectopic heart beat. Abdominal CT and MRI revealed a mass measuring 8 × 4 cm in the right adrenal gland. The diagnosis of pheochromocytoma was confirmed by elevated 24-hour urine levels of VMA, metanephrines and catecholamines as well as positive MIBG scan. The patient presented with classic clinical features of NF-1, which was confirmed by pathologic evaluation of an excised skin nodule. The patient underwent laparoscopic right adrenalectomy through a transabdominal approach and was discharged on the second postoperative day, being normotensive. The patient is normotensive without antihypertensive therapy 11 years after the procedure.ConclusionNowadays in the era of laparoscopy, patients with pheochromocytoma reach the operating theatre easier than in the past. Despite, the feasibility and oncological efficacy of the laparoscopic approach to the adrenals, continued long term follow-up is needed to establish the minimally invasive technique as the preferred approach. Furthermore, these patients should be further investigated for other neoplasias and stigmata of other neurocutaneous syndromes, taking into account the association of the familial pheochromo-cytoma with other familial basis inherited diseases.

The Evolution of Human Segmental Duplications and the Core Duplicon Hypothesis

Duplicated sequences are important sources of genetic instability and in the evolution of new gene function within species. Hominids have a preponderance of intrachromosomal duplications organized in an interspersed fashion, as opposed to tandem duplications, which are common in other mammalian genomes such as mouse, dog, and cow. Multiple lines of evidence, including sequence divergence, comparative primate genomes, and fluorescence in situ hybridization (FISH) analyses, point to an excess of segmental duplications in the common ancestor of humans and African great apes. We find that much of the interspersed human duplication architecture within chromosomes is focused around common sequence elements referred to as "core duplicons." These cores correspond to the expansion of gene families, some of which show signatures of positive selection and lack orthologs present in other mammalian species. This genomic architecture predisposes apes and humans not only to extensive genetic diversity, but also to large-scale structural diversity mediated by nonallelic homologous recombination. In humans, many de novo large-scale genomic changes mediated by these duplications are associated with neuropsychiatric and neurodevelopmental disease. We propose that the disadvantage of a high rate of new mutations is offset by the selective advantage of newly minted genes within the cores.

G.P.7.01 Combinatorial DHPLC analyses to identify point mutations in the dystrophin gene in 144 DMD/BMD patients

The molecular diagnosis of Duchenne and Becker muscular dystrophies is particularly difficult for the size of the dystrophin gene (2.4Mb with 79 exons and 8 promoters) and because the spectrum of disease-causing mutations is extremely wide and heterogeneous, with a high rate of new mutations. In the last few years different laborious DNA scanning techniques have been developed for the identification of these mutations since they have a pivotal importance in definition of the carrier status in females and for prenatal diagnosis.

A Novel Measurement of the Rate of Spontaneous Mutations in Human Myeloid Cells.

The mutation rate (μ) is likely to be a critical parameter in leukemogenesis, but has not previously been measured in human myeloid cells. Using the PIG-A gene as a sentinel, we have recently measured the mutation rate in B-lymphoblastoid cell lines (BLCLs) and shown that it is elevated in cell lines derived from lymphoid malignancies. Here we have measured μ in normal human CD34+ cells derived from cord blood samples that have been transduced with an AML-ETO fusion gene, growing under the influence of cytokines. PIG-A is an X-linked gene essential for the synthesis of glycosylphosphatidylinositol (GPI). Due to X-inactivation in females and hemizygosity in males, a single mutation can produce the GPI (−) phenotype. From patients with PNH, it is known that a broad spectrum of mutations can inactivate PIG-A. Mutants do not express GPI-linked surface proteins such as CD55 or CD59 and do not bind to the FLAER reagent (which binds GPI directly), but do express transmembrane proteins (e.g. CD45). To measure the rate of new mutations in vitro, we first flow-sorted each culture to collect CD59(+) cells, in order to exclude pre-existing mutants. Then we expanded the collected cells over 3 weeks; using cell counts, we calculated population doublings in culture (d), which ranged from 5.1 to 7.4. Cells were then stained sequentially with biotinylated FLAER, murine anti-CD55 and anti-CD59 antibodies, rabbit anti-mouse PE and streptavidin-PE secondary conjugates, and CD45-FITC. Live cells were identified by forward and side scatter, propidium iodide exclusion, and expression of CD45. The mutant frequency (f) was calculated as the number of GPI (−) cells [which do not bind anti-CD55, CD59 or FLAER] divided by the total number of cells analyzed. An average of 1.2 million cells were analyzed to detect rare mutants. The mutation rate was calculated by the formula μ = f/d. Among 5 cultures derived from 2 different cord blood samples, the mean mutation rate was 12.4 × 10−7 (range 5.1 to 21.4 × 10−7) per cell division. This value is consistent with mathematical models of the mutation rates in human populations as well as our previous experimental determination of μ in BLCLs. We also analyzed 6 cell lines in which p53 had been disrupted by various methods, including shRNA, a dominant-negative p53 mutant, and introduction of HPV E6/E7. Overall, disruption of p53 resulted in a 30% increase in the mutation rate (p=.02). We conclude that spontaneous mutations in human myeloid cultures are rare but measurable and that disruption of p53 results in a modest increase in μ. We predict that the ability to measure this critical parameter in human hematopoietic cells will facilitate the investigation of the role of specific oncogene and tumor suppressor mutations in inducing hypermutability.

Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome

The Coffin-Lowry syndrome (CLS) is a rare X-linked semidominant syndrome characterized by severe psychomotor retardation, facial dysmorphism, digit abnormalities and progressive skeletal deformations. CLS is caused by mutations in a gene located in Xp22.2, RPS6KA3. This gene encodes for a growth factor-regulated serine/threonine protein kinase, RSK2 (ribosomal S6 kinase 2), acting in the Ras-mitogen-activated protein kinase signaling pathway. Mutations in the RPS6KA3 gene are extremely heterogeneous and lead to premature termination of translation and/or to loss of phosphotransferase activity of the RSK2 protein. Screening for RSK2 mutations is essential in most cases to confirm the diagnosis as well as for genetic counseling. Here we present 44 novel mutations in RSK2 causing CLS. The overall number of CLS mutations reported now is 128. Thirty-three percent of mutations are missense mutations, 15% nonsense mutations, 20% splicing errors and 29% short deletion or insertion events. Only four large deletions have so far been found. They are distributed throughout the RPS6KA3 gene, and the majority has been found in a single family. This study further confirms the high rate of new mutations at the RSK2 locus. It is important to consider the possibility of mosaicism when providing genetic counseling in CLS families.

Subcutaneous Neurofibromas for Prognosis of NF-1

Neurofibromatosis 1 (NF-1) affects 1 in 3000 persons; this autosomal dominant condition has a high rate of new mutations and decreases life expectancy by about 15 years. Nodular and plexiform neurofibromas are associated with increased morbidity and mortality through transformation into malignant peripheral nerve sheath tumors and through compression of neighboring organs, leading to seizures, hydrocephalus, or spinal-cord …

Simultaneous occurrence of neurofibromatosis type 1 and tuberous sclerosis in a young girl

Neurofibromatosis type 1 and tuberous sclerosis are the two most common neurocutaneous disorders in humans. Both are transmitted as autosomal dominant conditions with a high rate of new mutations and similar clinical features. However, the two disorders have distinct and well-delineated genetic, biochemical, and physical findings. Simultaneous occurrence of these two conditions is rare. We report on a young girl who inherited both disorders, review similar cases reported in the world literature, and discuss possible implications of the presence of NF1 and TSC in the same individual.

Animal models for discovery and assessment of genetic determinants of osteoporosis.

Quantitative trait locus (QTL) mapping is the process of identifying, by both chromosomal position and effect, the major genetic contributors to natural-population (or interstrain) variation in the trait of inquiry. The polymorphic alleles, or variants, thus observed are distinct from variants turned up through mutagenesis screens in that each QTL allele exists in nature at a far higher level than could be maintained by the rate of new mutation. This tells us that none of the alleles confers a selective disadvantage, since even a 1% decrease in fitness is sufficient to eliminate that allele within a relatively short evolutionary time span. Thus, each QTL allele is equally normal, or ‘‘wild-type.’’ Several caveats should be noted. If a bone-relevant locus is invariant in a population, or does not happen to differ between the parental strains in an animal cross, it will be invisible to QTL detection. Thus, mapping studies that fail to detect a locus seen in another population or interstrain cross, or that find the same locus at lower significance, should not be interpreted as invalidating the previous positive observations. On the other hand, if a QTL is observed in multiple human populations and/or in the progeny of diverse mouse crosses between distantly related parental strains, that suggests the existence of a sustained polymorphism—in effect, an evolutionarily conserved mechanism for modulating a trait within populations. It may be of benefit to a population to include a range of phenotypes, such as high bone mass to increase bone strength and calcium reserves versus lower bone mass to improve speed. Table 1 summarizes graphically the regions implicated in several such studies of mouse interstrain cross progeny [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. Although simulation analysis to determine significance has yet to be performed, it is apparent that many loci have been recaptured in 2 or more crosses (see loci on chromosomes 1, 2, 7, 11, 13, 15, and 16). Such data can be used to estimate the number of polymorphic genes of comparable allelic effect [14]. The most significant development over the last decade, in the broad area of QTL mapping, was the determination of near-complete genomic sequences for humans and mice. These sequences, and tools for their alignment, have greatly facilitated positional cloning in each species and the transfer of information from one to the other. With regard specifically to bone QTLs, in just the last 5 years at least four laboratories [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13] have mapped murine QTLs for bone density (spinal or femoral, in each case measured at maturity or 4 months of age) and have used recurrent backcrossing guided by QTL-specific markers to create congenic lines. Such lines feature single blocks of ‘‘donor-strain’’ DNA isolated in the otherwise uniform genetic background of the recipient strain. In each laboratory, congenic lines have recently been tested and were found to display the expected differential allelic effects on the same and related bone traits (unpublished data and references [4, 11, 12, 13]). This is a significant validation of the QTL-mapping procedure and a stage at which some insights can be garnered through exploration of the broader phenotype of each QTL region. Considerable further investment of time and effort will be required to narrow these intervals, via generation and testing of recombinants, to spans comprising less than a few dozen genes. At that point, it will make sense to begin functional testing of individual positional-candidate genes based on both genomic location and putative roles in osteogenesis or its regulation.