Biomedical subjects
Publications and source records attributed to R Giorda.
We describe the clinical and molecular findings of a 6-year-old boy carrying a novel missense 964C>T mutation on the MECP2 gene. The patient shows moderate mental retardation with autistic features and epilepsy. His mother is heterozygous for the same mutation.
The ability to process and identify human faces matures early in life, is universal and is mediated by a distributed neural system. The temporal dynamics of this cognitive-emotional task can be studied by cerebral visual event-related potentials (ERPs) that are stable from midchildhood onwards. We hypothesized that part of individual variability in the parameters of the N170, a waveform that specifically marks the early, precategorical phases of human face processing, could be associated with genetic variation at the functional polymorphism of the catechol-O-methyltransferase (val(158)met) gene, which influences information processing, cognitive control tasks and patterns of brain activation during passive processing of human facial stimuli. Forty-nine third and fourth graders underwent a task of implicit processing of other children's facial expressions of emotions while ERPs were recorded. The N170 parameters (latency and amplitude) were insensitive to the type of expression, stimulus repetition, gender or school grade. Although limited by the absence of met- homozygotes among boys, data showed shorter N170 latency associated with the presence of 1-2 met158 alleles, and family-based association tests (as implemented in the PBAT version 2.6 software package) confirmed the association. These data were independent of the serotonin transporter promoter polymorphism and the N400 waveform investigated in the same group of children in a previous study. Some electrophysiological features of face processing may be stable from midchildhood onwards. Different waveforms generated by face processing may have at least partially independent genetic architectures and yield different implications toward the understanding of individual differences in cognition and emotions.
Molecular definition at the BAC level of an 8p dicentric chromosome and an 8p deleted chromosome is reported in a patient with two different cell lines. The dicentric, which differed from that generating the recurrent inv dup del(8p) for the location of its break point, originated during the paternal meiosis on the background of the classical 8p23.1 inversion polymorphism. The breakage of this dicentric gave rise to the 8p deleted chromosome which, as a result of the inversion, had two non-contiguous deletions. These findings confirm previous data on 1p distal deletions, showing that at least some of the deletions stem from the breakage of dicentric chromosomes. They suggest that non-contiguous deletions may be frequent among distal deletions. This type of rearrangement can easily be overlooked when two contiguous clones, one absent and the other present by FISH analysis, are taken as boundaries of the deletion break point; in this case only high resolution array-CGH will reveal their real frequency. The definition of such non-contiguous distal deletions is relevant for phenotype/karyotype correlations. There are historical examples of blunders caused by overlooking a second non-contiguous deletion. This paper shows how small scale structural variations, such as common polymorphic inversions, may cause complex rearrangements such as terminal deletions.
INTRODUCTION: The 22q13.3 deletion syndrome (MIM 606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. METHODS: The deletions were characterised by FISH, checked for other abnormalities by array-CGH, and confirmed by Real-Time PCR, and finally the breakpoints were cloned, sequenced, and compared. RESULTS: Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. The cases show a breakpoint within the same 15 bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. DISCUSSION: Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.
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We analyzed dystrophin alternative splicing events in a large number of Becker muscular dystrophy (BMD) affected individuals presenting major hot-spot deletions. Evidence is shown that altered splicing patterns in these patients do not directly result from the gene defect but probably derive from modifications in trans- rather than cis-acting factors. Several potential CUG-binding protein 2 (CUG-BP2) binding sites were found to be located in the dystrophin gene region encompassing exons 43-60 and CUG-BP2 transcript analysis indicated that not only expression levels are increased in dystrophic muscles but also that different CUG-BP2 isoforms are expressed. The possibility that CUG-BP2 might have a role in dystrophin splicing regulation is discussed.
Dopamine genes are candidate genes for dyslexia in the light of the well-known comorbidity between dyslexia and ADHD. Within-family association and linkage disequilibrium were tested between four genetic markers at DRD4, DRD3, DRD2, and DAT loci, and dyslexia, in a sample of 130 Italian dyslexic children, 16.9% of whom had comorbid ADHD. No evidence of either association or linkage disequilibrium was found, neither in the total sample nor in the comorbid subgroup. Negative results do not support a common genetic basis between these two disorders for these markers.
Dysferlin, the protein product of the dysferlin gene (DYSF), has been shown to have a role in calcium-induced membrane fusion and repair. Dysferlin is absent or drastically reduced in patients with the following autosomal recessive disorders: limb-girdle muscular dystrophy type 2B (LGMD-2B), Miyoshi myopathy (MM) and distal anterior compartment myopathy. To date, less than 45 mutations have been described in DYSF and a wide inter- and intra-familial variation in clinical phenotype has been associated with the same mutation. This observation underlines the relevance of any new report describing genotype/phenotype correlations in dysferlinopathic patient and families. Here we present the results of clinical, biochemical and genetic analysis performed on one MM and three LGMD Italian families. By screening the entire coding region of DYSF, we identified three novel mutations (two missense substitutions and one frame shift microdeletion). The possible existence of a founder effect for the Arg959Trp mutation in the Italian population is discussed.
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We have analysed splicing patterns in the human dystrophin gene region encoding the rod and cysteine-rich domains in normal skeletal muscle, brain and heart tissues. Sixteen novel alternative transcripts were identified, the majority of them being present in all three tissues. Tissue-specific variants were also identified, suggesting a functional role of transcriptional diversity. Transcript analysis in dystrophinopathic autoptic and bioptic specimens revealed that pre-mRNAs secondary structure formation and relative strength of exon/exon association play little or no role in directing alternative splicing events. This analysis also showed that independent deletion events leading to the loss of the same exons may be associated with transcriptional variability.
We recently showed that mutations in the CNGA3 gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all detected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Scandinavia and northern Italy, have a common origin.
The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.
The olfactory receptor (OR)-gene superfamily is the largest in the mammalian genome. Several of the human OR genes appear in clusters with > or = 10 members located on almost all human chromosomes, and some chromosomes contain more than one cluster. We demonstrate, by experimental and in silico data, that unequal crossovers between two OR gene clusters in 8p are responsible for the formation of three recurrent chromosome macrorearrangements and a submicroscopic inversion polymorphism. The first two macrorearrangements are the inverted duplication of 8p, inv dup(8p), which is associated with a distinct phenotype, and a supernumerary marker chromosome, +der(8)(8p23.1pter), which is also a recurrent rearrangement and is associated with minor anomalies. We demonstrate that it is the reciprocal of the inv dup(8p). The third macrorearrangment is a recurrent 8p23 interstitial deletion associated with heart defect. Since inv dup(8p)s originate consistently in maternal meiosis, we investigated the maternal chromosomes 8 in eight mothers of subjects with inv dup(8p) and in the mother of one subject with +der(8), by means of probes included between the two 8p-OR gene clusters. All the mothers were heterozygous for an 8p submicroscopic inversion that was delimited by the 8p-OR gene clusters and was present, in heterozygous state, in 26% of a population of European descent. Thus, inversion heterozygosity may cause susceptibility to unequal recombination, leading to the formation of the inv dup(8p) or to its reciprocal product, the +der(8p). After the Yp inversion polymorphism, which is the preferential background for the PRKX/PRKY translocation in XX males and XY females, the OR-8p inversion is the second genomic polymorphism that confers susceptibility to the formation of common chromosome rearrangements. Accordingly, it may be possible to develop a profile of the individual risk of having progeny with chromosome rearrangements.
We report an unusual presentation of a primary beta-sarcoglycanopathy (LGMD type 2E). A 12- year-old boy came to our attention after six episodes of exercise-induced myoglobinuria. Electromyogram showed mild myopathic features of the proximal lower limb muscles. Electrocardiogram was normal. Neurological examination revealed normal muscle strength and reduced deep tendon reflexes. A muscle biopsy showed rare regenerating fibers; the immunohistochemistry was normal for dystrophin, while all the sarcoglycans were diffusely decreased. Western blot analysis showed a relevant decrease of all sarcoglycan proteins and a mild dystrophin reduction. beta-Sarcoglycan gene analysis demonstrated a compound heterozygous status for these mutations: a novel A-T base pair substitution at nucleotide 85 in exon 2, changing the codon Arg to a stop codon; a C-T base pair substitution at nucleotide 272 in exon 3 changing a Arg to a Cys residue. We consider that exercise-induced myoglobinuria may be the presenting sign of primary beta-sarcoglycanopathy.
PURPOSE: To describe a family with X-linked congenital nystagmus and identify the genetic interval within which the gene is located. METHODS AND DESIGN: Clinical examination with genotyping of 30 individuals from a multi-generational Caucasian family with congenital nystagmus inherited in an X-linked pattern using markers from Xq26-q27, followed by linkage analysis and sequencing of a candidate gene, solute carrier family 25, member 14 (SLC25A14), in four affected individuals from four families linked to this region. RESULTS: The pattern of inheritance in the family was consistent with X-linkage with incomplete penetrance among carrier females. No affected males had affected sons. Based on the extended pedigree, the estimated penetrance among obligate female carriers (daughters of affected males) was 29% (6 of 21). Visual acuity among 15 affected individuals ranged from 20/20 to 20/70 (median 20/30). Clinical examinations, including electroretinography in two individuals, were otherwise normal except for the presence of nystagmus. Significant LOD scores (theta = 0) were found with markers DXS8057, DXS8044, DXS1047, DXS1062, DXS8072, and DXS8078, placing the gene within a approximately 5 cM interval flanked by DXS9909 and DXS1211 on the long arm of the X chromosome. Sequencing the candidate gene SLC25A14 in four affected individuals from four families linked to this region failed to reveal any mutations. CONCLUSIONS: NYS1 appears to be a common gene for familial congenital idiopathic nystagmus. Linkage analysis of this family further reduces the interval in which NYS1 is located.
Twelve genes which are expressed exclusively in pre-spore cells of Dictyostelium strain AX3 are expressed exclusively in pre-stalk cells of strain AX2. One gene has the opposite behavior: it is expressed in pre-stalk cells in AX3 and in pre-spore cells in AX2. The change in cell type specificity involves a change in the mechanism of control of gene expression. When they are expressed in pre-stalk cells, genes are controlled at the level of transcription, whilst in pre-spore cells, they are controlled at the level of mRNA stability. Genes expressed in pre-stalk cells in strain AX2, fused with an AX2 pre-spore specific promoter, become regulated at the level of mRNA stability. These findings indicate that at least a group of pre-stalk mRNAs possess the cis-destabilizing element typical of pre-spore mRNAs, though they are not destabilized in disaggregated cells. This is due to the fact that ribosomal protein S6, phosphorylation of which is responsible for controlling the stability of pre-spore mRNAs, is not dephosphorylated in disaggregated pre-stalk cells. These cells lack an S6 phosphatase activity which has been purified from disaggregated pre-spore cells.