Biomedical subjects

Maria Teresa Bonati

Publications and source records attributed to Maria Teresa Bonati.

8 recordsLinked to original sources

PubMed2026

A Family Exhibiting Autosomal Dominant Inheritance of Multiple Acyl-Coenzyme A (CoA) Dehydrogenase Deficiency (MADD) Disease.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.

Humans↗

PubMed2007

13q Deletion and central nervous system anomalies: further insights from karyotype-phenotype analyses of 14 patients.

BACKGROUND: Chromosome 13q deletion is associated with varying phenotypes, which seem to depend on the location of the deleted segment. Although various attempts have been made to link the 13q deletion intervals to distinct phenotypes, there is still no acknowledged consensus correlation between the monosomy of distinct 13q regions and specific clinical features. METHODS: 14 Italian patients carrying partial de novo 13q deletions were studied. Molecular-cytogenetic characterisation was carried out by means of array-comparative genomic hybridisation (array-CGH) or fluorescent in situ hybridisation (FISH). RESULTS: Our 14 patients showed mental retardation ranging from profound-severe to moderate-mild: eight had central nervous system (CNS) anomalies, including neural tube defects (NTDs), six had eye abnormalities, nine had facial dysmorphisms and 10 had hand or feet anomalies. The size of the deleted regions varied from 4.2 to 75.7 Mb. CONCLUSION: This study is the first systematic molecular characterisation of de novo 13q deletions, and offers a karyotype-phenotype correlation based on detailed clinical studies and molecular determinations of the deleted regions. Analyses confirm that patients lacking the 13q32 band are the most seriously affected, and critical intervals have been preliminarily assigned for CNS malformations. Dose-sensitive genes proximal to q33.2 may be involved in NTDs. The minimal deletion interval associated with the Dandy-Walker malformation (DWM) was narrowed to the 13q32.2-33.2 region, in which the ZIC2 and ZIC5 genes proposed as underlying various CNS malformations are mapped.

Abnormalities, Multiple↗

PubMed2006

Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with non-syndromic mental retardation.

Mental retardation (MR) is displayed by 57% of NF1 patients with microdeletion syndrome as a result of 17q11.2 region haploinsufficiency. We considered the cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) and oligodendrocyte-myelin glycoprotein (OMG) genes, mapping in the NF1 microdeleted region, as candidate genes for MR susceptibility. CDK5R1 encodes for a neurone-specific activator of cyclin-dependent kinase 5 (CDK5) involved in neuronal migration during central nervous system development. OMG encodes for an inhibitor of neurite outgrowth by the binding to the Nogo-66 receptor (RTN4R). CDK5R1 and OMG genes are characterized by large 3' and 5' untranslated regions (UTRs), where we predict the presence of several transcription/translation regulatory elements. We screened 100 unrelated Italian patients affected by unspecific MR for mutations in CDK5R1 and OMG coding regions and in their 3' or 5' UTRs. Four novel mutations and two novel polymorphisms for CDK5R1 and three novel mutations for OMG were detected, including two missense changes (c.323C>T; A108V in CDK5R1 and c.1222A>G; T408A in OMG), one synonymous codon variant (c.532C>T; L178L in CDK5R1), four variants in CDK5R1 3'UTR and two changes in OMG 5'UTR. All the mutations were absent in 370 chromosomes from normal subjects. The allelic frequencies of the two novel polymorphisms in CDK5R1 3'UTR were established in both 185 normal and 100 mentally retarded subjects. Prediction of mRNA and protein secondary structures revealed that two changes lead to putative structural alterations in the mutated c.2254C>G CDK5R1 3'UTR and in OMG T408A gene product.

Adolescent↗

PubMed2005

Trisomy 15q25.2-qter in an autistic child: genotype-phenotype correlations.

We report on the case of a male child with autistic disorder, postnatal overgrowth, and a minor brain malformation. Karyotyping and fluorescent in situ hybridization (FISH) analysis showed the presence of an extra copy of the distal portion of chromosome 15q (15q25.2-qter) transposed to chromosome 15p leading to 15q25.2-qter pure trisomy. This karyotype-phenotype study further supports the evidence for a specific phenotype related to trisomy 15q25 or 26-qter and suggests that distal chromosome 15q may be implicated in specific behavioral phenotypes.

Abnormalities, Multiple↗

PubMed2004

Genetics in restless legs syndrome.

Several studies on Restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that up to 60% report a positive family history. Investigations of single families with RLS have suggested an autosomal dominant mode of inheritance with variable expressivity, and some families show possible anticipation. At present, only one twin study is available, showing a high concordance rate (83.3%) between identical twins. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, but no significant findings have been reported. Genome-wide studies have been conducted to map genes that play a role in vulnerability to RLS. In a single French-Canadian family significant linkage was established on chromosome 12q. The susceptibility locus on chromosome 12q was not confirmed in two South Tyrolean families, or in our two Italian families. However, the efforts toward the identification of RLS genes must continue in order to obtain a better characterization of the syndrome and to identify new therapeutic strategies.

Genetic Predisposition to Disease↗

PubMed2003

Autosomal dominant restless legs syndrome maps on chromosome 14q.

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible desire to move the extremities associated with paraesthesia/dysaesthesia. These symptoms occur predominantly at rest and worsen at night, resulting in nocturnal insomnia and chronic sleep deprivation. In this paper, we show significant evidence of linkage to a new locus for RLS on chromosome 14q13-21 region in a 30-member, three-generation Italian family affected by RLS and periodic leg movements in sleep (PLMS). This is the second RLS locus identified so far and the first consistent with an autosomal dominant inheritance pattern. The new RLS critical region spans 9.1 cM, between markers D14S70 and D14S1068. The maximum two-point log of odds ratio score value, of 3.23 at theta = 0.0, was obtained for marker D14S288. The accurate clinical evaluation of RLS-affected, as well as unaffected, family members allowed for the configuring of RLS as a phenotypic spectrum ranging from PLMS to RLS. Motor component, both while awake and during sleep, was an important aspect of the phenotype in the family analysed. The complementary clinical and genetic studies on multiplex families are likely to be of the utmost importance in unfolding the complete expressivity of RLS phenotype spectrum.

Adolescent↗

PubMed2002

Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families.

Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family ( CHRNA4 and CHRNB2, coding for the alpha4 and beta2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization ( CHRNB2, 1q21; CHRNA2, 8p21; CHRNA6, CHRNB3, 8p11.2; CHRNA7, 15q14; CHRNA5/A3/B4, 15q24 and CHRNA4, 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for alpha2-7 and beta2-4 neuronal nAChR subunits could be responsible for ADNFLE.

Brain↗

PubMed2002

Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy.

Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction-amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for approximately 65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients.

Base Sequence↗