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Concept: Missense mutation


The purpose of this study was to elucidate the molecular basis of ocular albinism type I in a Chinese pedigree.

Concepts: DNA, Mutation, Allele, Point mutation, Missense mutation, Nonsense mutation, Albinism, Ocular albinism


Members of the Frizzled family of sevenpass transmembrane receptors signal via the canonical Wnt pathway and also via noncanonical pathways of which the best characterized is the planar polarity pathway. Activation of both canonical and planar polarity signaling requires interaction between Frizzled receptors and cytoplasmic proteins of the Dishevelled family; however, there has been some dispute regarding whether the Frizzled-Dishevelled interactions are the same in both cases. Studies looking at mutated forms of Dishevelled suggested that stable recruitment of Dishevelled to membranes by Frizzled was required only for planar polarity activity, implying that qualitatively different Frizzled-Dishevelled interactions underlie canonical signaling. Conversely, studies looking at the sequence requirements of Frizzled receptors in the fruit fly Drosophila melanogaster for canonical and planar polarity signaling have concluded that there is most likely a common mechanism of action. To understand better Frizzled receptor function, we have carried out a large-scale mutagenesis in Drosophila to isolate novel mutations in frizzled that affect planar polarity activity and have identified a group of missense mutations in cytosolic-facing regions of the Frizzled receptor that block Dishevelled recruitment. Interestingly, although some of these affect both planar polarity and canonical activity, as previously reported for similar lesions, we find a subset that affect only planar polarity activity. These results support the view that qualitatively different Frizzled-Dishevelled interactions underlie planar polarity and canonical Wnt signaling.

Concepts: Protein, Mutation, Point mutation, Missense mutation, Drosophila melanogaster, Drosophila, Wnt signaling pathway, Frizzled


Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α-subunit of the voltage-gated sodium channel, Na(v)1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V) and two sporadic mutations (I848T, V1316A). V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC(50) values of selective sodium channel blockers, lidocaine and mexiletine. The IC(50) for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two mutants which is comparable to the clinical observations.

Concepts: DNA, Mutation, Mutant, Action potential, Electrophysiology, Point mutation, Missense mutation, Erythromelalgia


Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

Concepts: DNA, Gene, Genetics, Mutation, Point mutation, Missense mutation, Nonsense mutation, Vastus lateralis muscle


Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Concepts: DNA, Genetics, Cancer, Mutation, Evolution, DNA repair, Point mutation, Missense mutation


Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive condition unlinked to mutations in SMN1. Through linkage analysis, homozygosity mapping, and exome sequencing in three unrelated SMA-PME-affected families, we identified a homozygous missense mutation (c.125C>T [p.Thr42Met]) in exon 2 of ASAH1 in the affected children of two families and the same mutation associated with a deletion of the whole gene in the third family. Expression studies of the c.125C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA. This reduced activity was able to normalize the ceramide level in Farber cells, raising the question of the pathogenic mechanism underlying the CNS involvement in deficient cells. Morpholino knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord. Our results reveal a wide phenotypic spectrum associated with ASAH1 mutations. An acid-ceramidase activity below 10% results in Farber disease, an early-onset disease starting with subcutaneous lipogranulomata, joint pain, and hoarseness of the voice, whereas a higher residual activity might be responsible for SMA-PME, a later-onset phenotype restricted to the CNS and starting with lower-motor-neuron disease.

Concepts: DNA, Gene, Genetics, Mutation, Evolution, Muscle, Point mutation, Missense mutation


Haemophilia A is an X-linked bleeding disorder caused by reduced or absent clotting factor VIII (FVIII) activity, determined by heterogeneous mutations in the F8 gene. Identification of these pathogenic mutations is important for genetic counseling and the assessment of clinical manifestations. Although more than 700 mutations of the F8 gene have been reported as responsible for severe haemophilia (FVIII: C<1%), the corresponding data is currently insufficient for southern Brazilian populations, and world reviews concerning these changes are scarce. Thirty-six unrelated severe haemophilia A patients who showed negative results for introns 22 and 1 inversions were studied for gross exon deletions and mutations there and in adjacent regions. Missense mutations were examined using molecular structural methods. The presence of FVIII inhibitors was also investigated. The results were compared with the information available from respectively 2878 and 1952 patients from all over the world. Twenty-nine different genetic changes were found, 16 of them novel. Seventeen of the carriers developed FVIII inhibitors, and molecular analysis suggested that Asp542Gly and Ser109Pro may interfere with calcium binding, whereas Leu2297Arg clearly affects the molecule's electrostatic surface. The main aetiological factor in the severe form of haemophilia seems to be missense mutations. Of all genetic changes occurring in these patients, large deletions are the most important in inhibitors formation.

Concepts: DNA, Genetics, Mutation, Blood, Coagulation, Point mutation, Missense mutation, Haemophilia A


ABSTRACT:: Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.

Concepts: Cancer, Mutation, Tumor, Frameshift mutation, Point mutation, Missense mutation, Nonsense mutation, Splice site mutation


Introduction: Leucine-rich repeat kinase 2 (LRRK2) has received considerable attention since the discovery of LRRK2 mutations in families with dominantly inherited Parkinson’s disease (PD) in 2004. The missense mutation G2019S is the most common LRRK2 mutation and has been identified in both familial and sporadic PD cases. The G2019S mutation enhances kinase activity suggesting that LRRK2 could be an attractive therapeutic target for PD and small-molecule ATP-competitive LRRK2 kinase inhibitors are one way to investigate this possibility. Areas covered: Currently, LRRK2 kinase inhibitors are being actively pursued by industry and academia. Herein, patents detailing the discovery of LRRK2 kinase inhibitors from 2006 through 2011 and the corresponding publications from 2006 through July of 2012 are summarized. Expert opinion: Wild-type and mutant forms of LRRK2 are currently being actively pursued as therapeutic targets for the potential treatment of PD. The increasing number of patent applications being filed for inhibitors of LRRK2 is a testament to this activity. Numerous distinct chemo-types have been reported as LRRK2 inhibitors with some demonstrating exceptional potency and selectivity for LRRK2 relative to other kinases. These compounds are being used as pharmacological ‘tools’ to elucidate the physiological and pathophysiological function of LRRK2 and it appears likely that some will be investigated for their potential therapeutic effects for the treatment of PD.

Concepts: Mutation, Protein kinase, Parkinson's disease, Point mutation, Missense mutation, Nonsense mutation, Patent, LRRK2


Vitamin D deficiency is a putative environmental risk factor for autism spectrum disorder (ASD). Besides, de novo mutations (DNMs) play essential roles in ASD. However, it remains unclear whether vitamin D-related genes (VDRGs) carry a strong DNM burden. For the 943 reported VDRGs, we analyzed publicly-available DNMs from 4,327 ASD probands and 3,191 controls. We identified 126 and 44 loss-of-function or deleterious missense mutations in the probands and the controls, respectively, representing a significantly higher DNM burden (p = 1.06 × 10(-5) ; odds ratio = 2.11). Specifically, 18 of the VDRGs were found to harbor recurrent functional DNMs in the probands, compared with only one in the controls. In addition, we found that 108 VDRGs with functional DNMs in the probands were significantly more likely to exhibit haploinsufficiency and genic intolerance (p < 0.0078). These VDRGs were also significantly interconnected and co-expressed, and also with other known ASD-risk genes (p < 0.0014), thereby forming a functional network enriched in chromatin modification, transcriptional regulation, and neuronal function. We provide straightforward genetic evidences for the first time that VDRGs with a strong degree of DNM burden in ASD and DNMs of VDRGs could be involved in the mechanism underlying in ASD pathogenesis.

Concepts: DNA, Genetics, Mutation, DNA repair, Point mutation, Missense mutation, Nonsense mutation, De novo