Exclusion of chromosome region 22q12.1-q12.3 as a second locus for Costello syndrome.
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Abnormalities, Multiple↗
Biomedical subjects
P Gasparini
Publications and source records attributed to P Gasparini.
Espin gene (ESPN) mutations associated with autosomal dominant hearing loss cause defects in microvillar elongation or organisation.
BACKGROUND: Espins are actin bundling proteins present in hair cell stereocilia. A recessive mutation in the espin gene (Espn) has been detected in the jerker mouse and causes deafness, vestibular dysfunction, and hair cell degeneration. More recently mutations in the human espin gene (ESPN) have been described in two families affected by autosomal recessive hearing loss and vestibular areflexia. OBJECTIVE: To report the identification of four additional ESPN mutations (S719R, D744N, R774Q, and delK848) in patients affected by autosomal dominant hearing loss without vestibular involvement. RESULTS: To determine whether the mutated ESPN alleles affected the biological activity of the corresponding espin proteins in vivo, their ability to target and elongate the parallel actin bundles of brush border microvilli was investigated in transfected LLC-PK1-CL4 epithelial cells. For three mutated alleles clear abnormalities in microvillar length or distribution were obtained. CONCLUSIONS: The results further strengthen the causative role of the espin gene in non-syndromic hearing loss and add new insights into espin structure and function.
Amino Acid Sequence↗
A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly.
Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant pleiotropic disorder, caused by mutations in the Connexin 43 gene (GJA1) [Paznekas et al. (2003): Am J Hum Genet 72:408-418], which is localized to human chromosome 6q22-q23. Here, we describe the identification of a novel heterozygous missense mutation in the GJA1 gene, (H194P) in an Italian family previously reported to be affected by isolated autosomal dominant microphthalmia [Vingolo et al. (1994): J Med Genet 31:721-725]. Careful clinical re-evaluation revealed that this family shows an atypical form of ODDD, characterized by the predominance of the ocular involvement and by the absence of hand and/or foot syndactyly. The mutation affects an amino acid residue localized in the second extracellular domain of the Cx43 protein and highly conserved across evolution. This finding confirms the highly variable phenotypic expression caused by GJA1 mutations.
Abnormalities, Multiple↗
A novel mutation in SACS gene in a family from southern Italy.
A form of autosomal recessive spastic ataxia (ARSACS) has been described in the Charlevoix and Saguenay regions of Quebec. So far a frameshift and a nonsense mutation have been identified in the SACS gene. The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS.
Adult↗
Guidelines and recommendations for testing of Cx26 mutations and interpretation of results.
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Adolescent↗
Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus.
Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs. They are inherited as autosomal dominant, autosomal recessive, and X-linked traits. Four Italian families with autosomal recessive pure spastic paraplegia are reported. We show evidence of linkage to the SPG5 locus on chromosome 8p and our data reduce the candidate interval for SPG5 to the11-cM interval spanned by D8S285 and D8S544. We also report the search for mutations in five genes located in the region and their exclusion as candidates for SPG5.
Adult↗
Erratum: Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.
Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five novel mutations (X781W, T132I, IVS2-2A>G, Y556H and 406del5).
Alleles↗
Seismic evidence of an extended magmatic sill under Mt. Vesuvius.
Mt. Vesuvius is a small volcano associated with an elevated risk. Seismic data were used to better define its magmatic system. We found evidence of an extended (at least 400 square kilometers) low-velocity layer at about 8-kilometer depth. The inferred S-wave (approximately 0.6 to 1.0 kilometer per second) and P-wave velocities (approximately 2.0 kilometer per second) as well as other evidence indicate an extended sill with magma interspersed in a solid matrix.
Journal Article↗
Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3.
Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. Fifty-two Finnish patients were homozygous for a termination mutation, Y100X; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.
Abnormalities, Multiple↗
MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss.
Mutations in the unconventional myosin VI gene, Myo6, are associated with deafness and vestibular dysfunction in the Snell's waltzer (sv) mouse. The corresponding human gene, MYO6, is located on chromosome 6q13. We describe the mapping of a new deafness locus, DFNA22, on chromosome 6q13 in a family affected by a nonsyndromic dominant form of deafness (NSAD), and the subsequent identification of a missense mutation in the MYO6 gene in all members of the family with hearing loss.
Amino Acid Sequence↗
New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.
Hereditary hemochromatosis usually results from C282Y homozygosity in the HFE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) has been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated by a homozygous nonsense mutation (Y250X). Here the identification of 2 new TFR2 mutations is reported. In a large inbred family from Campania, a frameshift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E60X) is identified. In a single patient with nonfamilial hemochromatosis, a T-->A transversion (T515A), which causes a Methionine-->Lysine substitution at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts-the alpha-transcript, which may encode a transmembrane protein, and the beta-transcript, a shorter, possibly intracellular variant. Based on their positions, the effects of the identified mutations on the 2 TFR2 forms are expected to differ. Y250X inactivates both transcripts, whereas E60X inactivates only the alpha-form. M172K has a complex effect: it causes a missense in the alpha-form, but it may also prevent the beta-form production because it affects its putative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homozygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations.
Adolescent↗
Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.
Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.
Adult↗
Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.
Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.
Amino Acid Sequence↗
DHPLC analysis of the MECP2 gene in Italian Rett patients.
Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which almost exclusively affects girls, with an estimated prevalence of one in 10,000-15,000 female births. Mutations in the methyl CpG binding protein 2 gene (MECP2) have been identified in roughly 75% of classical Rett girls. The vast majority of Rett cases (99%) are sporadic in origin, and are due to de novo mutations. We collected DNA samples from 50 Italian classical Rett girls, and screened the MECP2 coding region for mutations by denaturing high-performance liquid chromatography (DHPLC) and subsequent direct sequencing. DHPLC is a recently developed method for mutation screening which identifies heteroduplexes formed in DNA samples containing mismatches between wild type and mutant DNA strands, combining high sensitivity, reduced cost per run, and high throughput. In our series, 19 different de novo MECP2 mutations, eight of which were previously unreported, were found in 35 out of 50 Rett girls (70%). Seven recurrent mutations were characterized in a total of 22 unrelated cases. Initial DHPLC screening allowed the identification of 17 out of 19 different mutations (90%); after optimal conditions were established, this figure increased to 100%, with all recurrent MECP2 mutations generating a characteristic chromatographic profile. Detailed clinical data were available for 27 out of 35 mutation carrying Rett girls. Milder disease was detectable in patients carrying nonsense mutation as compared to patients carrying missense mutations, although this difference was not statistically significant (P = 0.077).
Chromatography, High Pressure Liquid↗
Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.
Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five new mutations (X871M, T132I, IVS1-2A>G, Y556H and 406del5).
Alleles↗
Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation.
We report a direct DNA sequencing analysis of the MECP2 gene undertaken on a further 64 Italian patients with Rett syndrome by using a LICOR 4200 Automated Sequencer. All of the girls entering the study had a consistent clinical diagnosis for this disorder. All coding regions and the flanking intronic splice site sequences were amplified as three non-overlapping fragments by using both forward and reverse primers. The results were then compared to the MECP2 reference sequences published in GenBank. Mutations of the MECP2 gene were identified in 64 of 75 (85.33%) unrelated sporadic Rett syndrome girls. Genotype/phenotype correlation studies, in particular in groups of patients with the same mutation, did not offer definitive and interesting data.
Adolescent↗
The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.
In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
Abnormalities, Multiple↗
Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.
Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder.
Adult↗