Neurologic phenotypes associated with acanthocytosis.

The term "neuroacanthocytosis" is normally used to refer to autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome, but there are other movement disorders in which erythrocyte acanthocytosis may also be seen, such as Huntington disease-like 2 and pantothenate kinase-associated neurodegeneration. Disorders of serum lipoproteins such as Bassen-Kornzweig disease form a distinct group of neuroacanthocytosis syndromes in which ataxia is observed, but movement disorders are not seen. Genetic testing has enabled us to distinguish between these disorders, even when there are considerable similarities between phenotypes. Improved detection is important for accurate genetic counseling, for monitoring for complications, and, it is hoped, for implementing causal treatments, once these become available. As in other neurodegenerative conditions, animal models are a promising strategy for the development of such therapies.

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

A conserved sorting-associated protein is mutant in chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.

McLeod neuroacanthocytosis: genotype and phenotype.

McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

Hereditary spastic paraplegia associated with peripheral neuropathy: a distinct clinical and genetic entity.

Hereditary motor and sensory neuropathy type V is a very rare disease in which hereditary spastic paraplegia is associated with peripheral motor and sensory neuropathy. The symptomatic onset of the disorder is usually in the second decade of life or later and the course is progressive over many years. Hereditary motor and sensory neuropathy type V is inherited as an autosomal dominant trait usually showing incomplete penetrance. So far, no molecular data are available in the literature about this disease. In our study we present clinical and molecular data from a large Italian family displaying hereditary motor and sensory neuropathy type V. Taking into account the clinical features in this family, we have performed a linkage analysis for markers strictly associated with all the known loci for autosomal dominant and autosomal recessive forms of hereditary spastic paraplegia and hereditary motor and sensory neuropathy type II, and have found no linkage to these loci. Our study suggests that hereditary motor and sensory neuropathy type V is not only a distinct clinical entity but also a distinct genetic entity.

A comprehensive, high-resolution genomic transcript map of human skeletal muscle.

We present the Human Muscle Gene Map (HMGM), the first comprehensive and updated high-resolution expression map of human skeletal muscle. The 1078 entries of the map were obtained by merging data retrieved from UniGene with the RH mapping information on 46 novel muscle transcripts, which showed no similarity to any known sequence. In the map, distances are expressed in megabase pairs. About one-quarter of the map entries represents putative novel genes. Genes known to be specifically expressed in muscle account for <4% of the total. The genomic distribution of the map entries confirmed the previous finding that muscle genes are selectively concentrated in chromosomes 17, 19, and X. Five chromosomal regions are suspected to have a significant excess of muscle genes. Present data support the hypothesis that the biochemical and functional properties of differentiated muscle cells may result from the transcription of a very limited number of muscle-specific genes along with the activity of a large number of genes, shared with other tissues, but showing different levels of expression in muscle. [The sequence data described in this paper have been submitted to the EMBL data library under accession nos. F23198-F23242.]

The preliminary transcript map of a human skeletal muscle.

By sequencing 11,405 individual expressed sequence tags (ESTs) from a cDNA library of a human skeletal muscle, we identified 1945 individual transcripts, 725 of which showed no correspondence with known human genes. We report here the chromosomal localization of 267 of these, obtained by radiation hybrid (RH) mapping. The map position of additional 242 ESTs from the same library, corresponding to known human genes, is also reported. The resulting information provides a preliminary genomic transcriptional profile of a human muscle. Several genes occur in clusters on different chromosomes. Moreover, chromosomes 17, 19, 21 and X appear to be significantly rich in muscle ESTs. By analysing several collections of ESTs from different tissues, we observed significant deviations in the distribution of ESTs by chromosome in fetal heart, adult brain and adult retina, supporting the hypothesis that a non-random localization of genes expressed in specific tissues might not be uncommon. The selective concentration of expressed genes in some chromosomes and in specific chromosomal subregions in a given tissue might reflect the existence of batteries of genes under the same control mechanisms, regulating tissue-specific gene expression.

Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast.

In this paper the chromosomal localization of the human skeletal muscle genes Troponin-I slow-twitch (TNNI1), Troponin-I fast-twitch (TNNI2), and Troponin-C fast (TNNC2) and the refinement of the position for alpha-Tropomyosin (TPM1) and beta-Tropomyosin (TPM2) are reported. By radiation hybrid mapping, TPM1 was assigned to chromosome 15q22.1, TPM2 to chromosome 9p13.2-p13.1, TNNI1 to chromosome 1q31.3, TNNI2 to chromosome 11p15.5, and TNNC2 to chromosome 20q12-q13.11. The genomic distribution of these genes is discussed, with particular emphasis on the cluster organization of the Troponin genes.

Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5.

The mitogen-activated protein kinase (MAPK) signaling cascade is one of the most important mechanisms for the cytoplasmic transduction of extracellular signals. We report the chromosomal localization of the human MEK1, MEK3, MEK4 and MEKK5 genes, involved in the MAPK cascade. Using radiation hybrid mapping, MEK1 was assigned to chromosome 15q22.1 --> q22.33, MEK3 to chromosome 17q11.2, MEK4 to chromosome 17p12, and MEKK5 to chromosome 6q22.33.

Identification of genetic factors for Alachlor tolerance in maize by molecular markers analysis.

Genetic factors controlling tolerance to the herbicide Alachlor in maize were localised by means of two different strategies. In the first approach, backcross (BC) plants, derived from pollen which had been subjected to selective pressure for resistance to the herbicide, were analysed for segregation distortion at 47 RFLP loci and compared to BC plants obtained from non-selected pollen. Preferential transmission of five chromosomal regions where putative QTLs (Quantitative Trait Loci) are localised was revealed in the BC plants from selected pollen. A second approach was based on a classical linkage analysis for segregation of the same set of RFLPs and factors controlling the trait, in a BC population of 210 individuals, by means of regression analysis. This study detected seven significant loci in four genomic regions. Overall, two loci revealed both segregation distortion and association with the expression of the trait, indicating linkage to genes expressed in both gametophytic and sporophytic phase. Three chromosomal regions appeared to carry factors involved in plant tolerance to Alachlor which are not expressed in pollen. Conversely, three loci were linked to factors selectable in pollen, but did not reveal significant association with tolerance in the plant in the segregating populations.