C19orf12 mutation leads to a pallido-pyramidal syndrome.

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles.

INTRODUCTION: Triple-negative breast cancers (TNBCs) are characterised by lack of expression of hormone receptors and epidermal growth factor receptor 2 (HER-2). As they frequently express epidermal growth factor receptors (EGFRs), anti-EGFR therapies are currently assessed for this breast cancer subtype as an alternative to treatments that target HER-2 or hormone receptors. Recently, EGFR-activating mutations have been reported in TNBC specimens in an East Asian population. Because variations in the frequency of EGFR-activating mutations in East Asians and other patients with lung cancer have been described, we evaluated the EGFR mutational profile in tumour samples from European patients with TNBC. METHODS: We selected from a DNA tumour bank 229 DNA samples isolated from frozen, histologically proven and macrodissected invasive TNBC specimens from European patients. PCR and high-resolution melting (HRM) analyses were used to detect mutations in exons 19 and 21 of EGFR. The results were then confirmed by bidirectional sequencing of all samples. RESULTS: HRM analysis allowed the detection of three EGFR exon 21 mutations, but no exon 19 mutations. There was 100% concordance between the HRM and sequencing results. The three patients with EGFR exon 21 abnormal HRM profiles harboured the rare R836R SNP, but no EGFR-activating mutation was identified. CONCLUSIONS: This study highlights variations in the prevalence of EGFR mutations in TNBC. These variations have crucial implications for the design of clinical trials involving anti-EGFR treatments in TNBC and for identifying the potential target population.

T cell division and death are segregated by mutation of TCRbeta chain constant domains.

We have studied the role of the T cell receptor (TCR) beta chain transmembrane and cytoplasmic domains (betaTM/Cyto) in T cell signaling. Upon antigen stimulation, T lymphocytes expressing a TCR with mutant and betaTM and Cyto domains accumulate in large numbers and are specifically defective in undergoing activation-induced cell death (AICD). The mutant TCR poorly recruits the protein adaptor Carma-1 and is subsequently impaired in activating NF-kappaB. This signaling defect leads to a reduced expression of Fas ligand (FasL) and to a reduction in AICD. These beta chain domains are involved in discriminating cell division and apoptosis.

Neuronal calcium channel mutation in a patient with congenital ataxia and attacks of hemiplegic migraine with cerebral edema

Background: Familial Hemiplegic Migraine (FHM), characterized by a prolonged unilateral hemiparesis, mainly results from mutations in the alpha-1a subunit of the calcium channel gene CACNA1A that can also cause two other dominantly inherited neurological disorders, Episodic Ataxia type 2 (EA2, with sometimes migrainous headaches) and Spinocerebellar Ataxia type 6 (SCA6, late-onset and progressive). A same mutation can have different clinical expression in a family (hemiplegic migraine, migraine-coma, cerebellar ataxia). CACNA1A mutations in FHM are usually missense, leading to gain-of-function, while truncating mutations leading to loss-of-function are usually associated with EA2. Case report: This 9-year-old girl was seen as a baby for hypotonia and transient vertical nystagmus. Her first brain MRI was normal. She evolved as a congenital ataxia, but since the age of two, she had attacks of coma, hemiparesis (either side), partial seizures, dystonic movements and fever. Attacks were initially triggered by minor head bumps, subsequently spontaneous. Brain MRIs in the acute stage always showed transient unilateral hemisphere swelling. Follow-up images revealed atrophic lesions in the temporo-occipital regions and cerebellar atrophy. A prophylactic trial with flunarizine was ineffective. Acetazolamide was recently introduced. Methods: Since our patient shared features of both FHM and EA2, we studied the CACNA1A gene by direct sequencing in the patient's and parents' DNA. Results: We identified an unreported de novo heterozygous deletion of three base pairs (c.4503_4505delCTT) predicting the deletion of one amino acid (p.Phe1502del). The CACNA1A protein contains 4 domains, each formed by six transmembrane segments. The deletion is located in a highly conserved region in segment 6 (S6) of the third domain. Mutations in S6 segments of calcium channels change single-channel conductance and channel selectivity, most resulting in loss-of-function. Outlook: In vitro expression studies of the identified mutation are underway, aiming at understanding its functional consequences and finding an efficient treatment.

A hypomorphic mutation in lpin1 induces progressively improving peripheral neuropathy in the rat

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat with a mutated Lpin1 gene (Lpin11Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubr rats are characterized by hindlimb paralysis that is detectable from the second postnatal week. Sequencing of Lpin1 identified a missense mutation in the 5'-end splice site of exon 18 resulting in mis-splicing, a reading frame shift and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. As a consequence, Lpin11Hubr rats develop hypomyelination rather than the pronounced demyelination defect characteristic of Lpin1fld/fld mice, which carry a null allele for Lpin1. Furthermore, histological and molecular analyses revealed that this lesion improve in older Lpin11Hubr rats as compared to young Lpin11Hubr rats and Lpin1fld/fld mice. The observed differences between the murine Lpin1fld/fld mutant, with a complete loss of Lipin 1 function, and the Lpin1Hubr rat, with a truncated PAP1 activitydeficient form of Lipin 1, provide additional evidence for suggested non-enzymatic Lipin1 function residing outside of its PAP1 domain. While we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into pathogenicity of recently identified human Lpin1 mutations. *These authors contributed equally.

New wheat genotypes tolerant to aluminum toxicity obtained by mutation induction

Seed from the sensitive wheat (Triticum aestivumL.) cultivar Anahuac was treated to gamma-ray irradiation and eleven Al3+ tolerant mutants selected. The objective was to compare these mutants to the original Anahuac and to the tolerant wheat cultivars IAC-24 and IAC-60 from 1994 to 1996 in acid (Capão Bonito) and limed (Monte Alegre do Sul) soil field trials, in the State of São Paulo, Brazil. Grain yield and agronomic characteristics were analyzed. All the mutant lines yielded higher than the sensitive Anahuac cultivar in the acid soils of Capão Bonito. Under limed soil conditions, 10 mutants had a similar yield to the original sensitive cultivar and one a lower yield. The majority of the mutants were similar in yield to the tolerant cultivars IAC-24 and IAC-60 under both conditions. Some of the mutants showed altered agronomic characteristics, but these alterations did not generally influence the grain yield. The results indicated that tolerant lines with good characteristics may be obtained from a susceptible cultivar by mutation induction, thus allowing cropping under conditions where Al3 + is a limiting factor.

Clinical and electrophysiological recovery in Leber hereditary optic neuropathy with G3460A mutation.

To report a case of clinical and electrophysiological recovery in Leber hereditary optic neuropathy (LHON) with G3460A Mutation. A 10-year-old boy with a three-month history of painless bilateral sequential visual loss upon presentation underwent visual acuity (diminished), anterior and posterior segment examination (normal), fluorescein angiography (normal), Goldman kinetic perimetry (bilateral central scotomata), genetic (a point G3460A mutation) and electrophysiological investigation (undetectable pattern visual evoked potentials (VEP); low amplitude, broadened and reduced flash VEPs and loss of the N95 component in the pattern electroretinograms). Diagnosis of LHON was made. Eighteen months later vision and electrophysiological tests results began spontaneously improving. Kinetic perimetry revealed reduced density and size of scotomata. Two years later, there had been further electrophysiological improvement. This report describes both clinical and electrophysiological improvement in LHON with G3460A mutation.

Mutation patterns of amino acid tandem repeats in the human proteome

Background: Amino acid tandem repeats are found in nearly one-fifth of human proteins. Abnormal expansion of these regions is associated with several human disorders. To gain further insight into the mutational mechanisms that operate in this type of sequence, we have analyzed a large number of mutation variants derived from human expressed sequence tags (ESTs).Results: We identified 137 polymorphic variants in 115 different amino acid tandem repeats. Of these, 77 contained amino acid substitutions and 60 contained gaps (expansions or contractions of the repeat unit). The analysis showed that at least about 21% of the repeats might be polymorphic in humans. We compared the mutations found in different types of amino acid repeats and in adjacent regions. Overall, repeats showed a five-fold increase in the number of gap mutations compared to adjacent regions, reflecting the action of slippage within the repetitive structures. Gap and substitution mutations were very differently distributed between different amino acid repeat types. Among repeats containing gap variants we identified several disease and candidate disease genes.Conclusion: This is the first report at a genome-wide scale of the types of mutations occurring in the amino acid repeat component of the human proteome. We show that the mutational dynamics of different amino acid repeat types are very diverse. We provide a list of loci with highly variable repeat structures, some of which may be potentially involved in disease.

Para-arterial sparing phenotype in Leber congenital amaurosis associated with homozygous p.R108X SPATA-7 mutation

Purpose: To describe the genotype/phenotype correlation associated with homozygous p.R108X mutation in the SPATA7 gene. Methods: A consanguineous nuclear family of Ethiopian origin was ascertained for genotypic and phenotypic characterization, including fundus photography, fundus autofluorescence (FAF), and full-field ERG. Molecular diagnosis was performed using a microarray. Results: Two of the 5 family members were affected with LCA. A homozygous c.322C>T (p.R108X) mutation in exon 5 of SPATA-7 was identified in both of them. The patients were 4 and 11 years old, respectively. Fundus examination revealed an unremarkable macular area, but optic nerve pallor, attenuated vascular calibre and deep retinal nummular deposits with para-arterial sparing predominant in the midperiphery. FAF showed multiples areas of hyperautofluorescence, corresponding to the deep retinal deposits. ERG was not recordable in the young patient, and showed severe rods/cones dysfunction in the older one. Conclusions: The literature describing genotype/phenotype correlation of SPATA-7 mutations in Leber congenital amaurosis (LCA) is still limited. We report the occurrence of para-arterial sparing in two sibs with SPATA7-linked LCA which may represent a clinical marker of this condition.

Acampomelic Form of Campomelic Dysplasia with SOX9 Missense Mutation.

Campomelic dysplasia is a skeletal dysplasia characterized by flat face, Pierre Robin sequence, shortening and bowing of long bones and club feet. The authors describe a case of "acampomelic" campomelic dysplasia that differs from classical campomelic dysplasia by the absence of bone bowing. This condition is among the most common skeletal dysplasias but is often misdiagnosed in the absence of overt campomelia.

Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections.

OBJECTIVE: To identify disease causing mutation in three generations of a Swiss family with pattern dystrophy and high intrafamilial variability of phenotype. To assess the effect of intravitreal ranibizumab injections in the treatment of subfoveal choroidal neovascularization associated with pattern dystrophy in one patient. METHODS: Affected family members were ascertained for phenotypic and genotypic characterization. Ophthalmic evaluations included fundus photography, autofluorescence imaging, optical coherence tomography, and International Society for Clinical Electrophysiology of Vision standard full-field electroretinography. When possible family members had genetic testing. The proband presented with choroidal neovascularization and had intravitreal injections as needed according to visual acuity and optical coherence tomography. RESULTS: Proband had a multifocal type pattern dystrophy, and his choroidal neovascularization regressed after four intravitreal injections. The vision improved from 0.8 to 1.0, and optical coherence tomography showed complete anatomical restoration. A butterfly-shaped pattern was observed in her cousin, whereas a fundus pulverulentus pattern was seen in a second cousin. Aunt had a multifocal atrophic appearance, simulating geographic atrophy in age-related macular degeneration. The Y141C mutation was identified in the peripherin/RDS gene and segregated with disease in the family. CONCLUSION: This is the first report of marked intrafamilial variation of pattern dystrophy because of peripherin/RDS Y141C mutation. Intravitreal ranibizumab injections might be a valuable treatment for associated subfoveal choroidal neovascularization.

Populations with elevated mutation load do not benefit from the operation of sexual selection.

Theory predicts that if most mutations are deleterious to both overall fitness and condition-dependent traits affecting mating success, sexual selection will purge mutation load and increase nonsexual fitness. We explored this possibility with populations of mutagenized Drosophila melanogaster exhibiting elevated levels of deleterious variation and evolving in the presence or absence of male-male competition and female choice. After 60 generations of experimental evolution, monogamous populations exhibited higher total reproductive output than polygamous populations. Parental environment also affected fitness measures - flies that evolved in the presence of sexual conflict showed reduced nonsexual fitness when their parents experienced a polygamous environment, indicating trans-generational effects of male harassment and highlighting the importance of a common garden design. This cost of parental promiscuity was nearly absent in monogamous lines, providing evidence for the evolution of reduced sexual antagonism. There was no overall difference in egg-to-adult viability between selection regimes. If mutation load was reduced by the action of sexual selection in this experiment, the resultant gain in fitness was not sufficient to overcome the costs of sexual antagonism.