Biomedical subjects

Francesco Brancati

Publications and source records attributed to Francesco Brancati.

At least 19 recordsLinked to original sources

PubMed2026

Global downstream BMP15 pathway analysis in human ovarian granulosa cells reveals novel genetic variations associated with primary ovarian insufficiency.

OBJECTIVES: Primary ovarian insufficiency (POI) is a fertility disorder with a well-established genetic component, but many cases still remain idiopathic. Approximately 1.5-12% of patients with POI can carry a variant in the BMP15 gene, depending on the population and the diagnostic criteria. We hypothesize that genetic variations within pathways downstream of BMP15 activity in ovarian granulosa cells (GCs) may contribute to unexplained cases of POI. The main goal of this study is to identify novel variants associated with POI in genes induced by BMP15 in GCs. STUDY DESIGN: Primary cultures of human GCs were stimulated with recombinant human BMP15. Microarray analysis profiled the BMP15-induced transcriptome in GCs. Validation was achieved by qPCR and immunoblot. Further, target exome sequencing of the differentially expressed genes was performed on 64 women with early POI onset in search of novel variants. MAIN OUTCOME MEASURES: Transcriptome profiling of human GCs stimulated with BMP15 and target exome sequencing in women with early onset of POI. RESULTS: Transcriptome analysis revealed significant upregulation of 19 genes (p < 0.05). Ontology analysis of these genes converged towards two main pathways: TGF-beta signaling and regulation of stem cell pluripotency. Target exome sequencing identified six novel rare variants in five BMP15-induced genes (SAMD11, SMAD6, ID1, USP35, GPCR137C) in 9 of the 64 women with early POI (14%). CONCLUSIONS: BMP15 action in human ovarian GCs defines TGF-beta signaling and pluripotency fate in ovarian follicles. In addition, this study uncovers new potential candidate genes for the pathogenesis of POI.

Humans↗

PubMed2007

A novel patient with Cooks syndrome supports splitting from "classic" brachydactyly type B.

We report on a 2-year-old girl affected by an isolated form of brachydactyly type B (BDB)-like malformation of the limbs consistent with Cooks syndrome (CS). A literature review was carried out in an attempt to delineate the CS clinical spectrum and separate it from BDB. The two conditions can be differentiated on clinical, radiological, and genetic grounds. In particular, CS shows a characteristic pattern of ungueal and phalangeal anomalies. In the hands, all rays are involved to a similar extent with bulbous tips. The feet are generally more severely affected than the hands. Involvement of the nails appears to be a primary feature and not secondary to phalangeal hypo/aplasia. Also, radial and ulnar rays are similarly affected. The CS clinical spectrum is expanded to include ungueal tumor-like lesions, observed in the present patient.

Child, Preschool↗

PubMed2007

Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm.

Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYT1) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYT1 as previously described in an Icelandic population. We have also found global significant DYT1 haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia.

Blepharospasm↗

PubMed2007

Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum.

Autosomal recessive parkinsonism is a genetic condition closely resembling Parkinson disease, the only distinguishing features being an earlier age at onset and a slower disease progression. Three causative genes have been identified so far. While exon rearrangements are frequently encountered in the Parkin gene, most PINK1 mutations are represented by single nucleotide changes. We report a sporadic parkinsonian patient carrying a deletion of the entire PINK1 gene and a splice site mutation (g.15445_15467del23) which produces several aberrant mRNAs. This report expands the genotypic spectrum of PINK1 mutations, with relevant implications for molecular analysis of this gene.

Amino Acid Sequence↗

PubMed2006

KBG syndrome.

KBG syndrome is a rare condition characterised by a typical facial dysmorphism, macrodontia of the upper central incisors, skeletal (mainly costovertebral) anomalies and developmental delay. To date, KBG syndrome has been reported in 45 patients. Clinical features observed in more than half of patients that may support the diagnosis are short stature, electroencephalogram (EEG) anomalies (with or without seizures) and abnormal hair implantation. Cutaneous syndactyly, webbed short neck, cryptorchidism, hearing loss, palatal defects, strabismus and congenital heart defects are less common findings. Autosomal dominant transmission has been observed in some families, and it is predominantly the mother, often showing a milder clinical picture, that transmits the disease. The diagnosis is currently based solely on clinical findings as the aetiology is unknown. The final diagnosis is generally achieved after the eruption of upper permanent central incisors at 7-8 years of age when the management of possible congenital anomalies should have been already planned. A full developmental assessment should be done at diagnosis and, if delays are noted, an infant stimulation program should be initiated. Subsequent management and follow-up should include an EEG, complete orthodontic evaluation, skeletal investigation with particular regard to spine curvatures and limb asymmetry, hearing testing and ophthalmologic assessment.

Abnormalities, Multiple↗

PubMed2006

Antenatal presentation of the oculo-auriculo-vertebral spectrum (OAVS).

We describe a fetus with abnormal ultrasound (US) imaging at 20 weeks showing hydrocephalus and radial aplasia. Post-mortem examination followed pregnancy termination and confirmed the diagnosis of oculo-auriculo-vertebral spectrum (OAVS). To delineate the pattern of prenatal features in OAVS, we reviewed 20 published fetuses showing abnormal US and/or magnetic resonance imaging. Gestational age at diagnosis ranged from 14 to 34-35 weeks. Cephalic abnormalities were found in only 52.4% (i.e., micro/anophthalmia, ear anomalies, hemifacial microsomia, and facial cleft). CNS defects occurred in 47.6% (i.e., hydrocephalus, occipital encephalocele, cerebellar hemisphere/vermis hypoplasia, and lipoma of the corpus callosum), together with abnormal amniotic fluid volume (AFV), either poly- or oligohydramnios. Nineteen percent had congenital heart disease, mainly atrioventricular septal defect. Hydroureteronephrosis, radial aplasia, lung, and kidney agenesis were additional findings. Recurrent patterns of anomalies included multiple asymmetric facial lesions (i.e., hemifacial microsomia, ipsilateral micro/anophthalmia, malformed ear) and CNS (particularly hydrocephalus) plus AFV abnormalities. In addition, prognosis of prenatally detected OAVS patients resulted more severe than generally observed in this condition.

Adult↗

PubMed2006

Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome.

Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.

Animals↗

PubMed2006

Hypochondrogenesis.

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Bone Diseases, Developmental↗

PubMed2006

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.

OBJECTIVE: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. METHODS: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. RESULTS: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. INTERPRETATION: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Majewski osteodysplastic primordial dwarfism type II (MOPD II) complicated by stroke: clinical report and review of cerebral vascular anomalies.

We report on a 2 9/12-year-old boy with disproportionate short stature, microcephaly, subtle craniofacial dysmorphisms, and generalized skeletal dysplasia, who developed a left hemiparesis. Brain neuroimaging disclosed a complex cerebral vascular anomaly (CVA) with stenosis of the right anterior cerebral artery and telangiectatic collateral vessels supplying the cerebral cortex, consistent with moyamoya disease. Based on clinical and skeletal features, a diagnosis of Majewski osteodysplastic primordial dwarfism type II (MOPD II) was established. Review of 16 published patients with CVA affected by either Seckel syndrome or MOPD II suggested that CVA is preferentially associated to the latter subtype affecting about 1/4 of the patients.

Abnormalities, Multiple↗

PubMed2005

A novel family with an unusual early-onset generalized dystonia.

We report on an Italian family in which three brothers and their maternal grandfather had a generalized early-onset dystonia with mild parkinsonian signs. Genetic testing excluded the rapid-onset dystonia-parkinsonism locus (DYT12; OMIM*128235), autosomal recessive Parkin locus (PARK2; OMIM *602544), and DYT1 dystonia. Three affected siblings were found to share an identical haplotype at the X-linked dystonia-parkinsonism locus (XDP; Lubag; OMIM*314250). This haplotype differed from the haplotype observed in Filipino patients, ruling out the hypothesis of a common underlying mutation. In addition, direct sequencing analysis of the putative disease causing changes observed in Filipino patients were not found in the Italian patients. The condition we describe could be a newly recognized dystonia syndrome with parkinsonism.

Adult↗

PubMed2005

A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies.

PURPOSE: To characterize clinically and genetically a four-generation Italian family with autosomal dominant retinal dystrophy. METHODS: Thirty-seven family members underwent a detailed ophthalmologic investigation, comprising visual acuity determination, fundoscopy, electroretinogram, and electrooculogram. A genome-wide scan was performed, and three candidate genes mapping to the linked region were screened for mutations by direct sequencing. RESULTS: Nineteen individuals were affected by cone-rod dystrophy and four by cone dystrophy, whereas, in another subject, the diagnosis was compatible with central areolar choroidal dystrophy. The genome-wide search allowed mapping the disease locus to chromosome 6, region p12.2-p21.1, with a maximum lod score of 6.71. Analysis of key recombinants in affected individuals placed the locus to a 12-Mb region flanked by newly generated markers 6-41025 and 6-52969. Assuming complete penetrance, recombinations in two healthy individuals defined a smaller critical region of 3.7 Mb between markers 6-42153 and D6S459. Three genes mapping within the linked interval (RDS, GUCA1A, and GUCA1B) were considered excellent candidates because of their involvement in distinct forms of retinal dystrophies. However, mutation analyses of these genes failed to identify pathogenetic mutations. CONCLUSIONS: The significant lod scores obtained and the absence of mutations in RDS, GUCA1A, and GUCA1B support the existence of a novel, yet unidentified gene responsible for retinal dystrophy within the chromosome 6 cluster.

Adult↗

PubMed2004

KBG syndrome in a cohort of Italian patients.

KBG syndrome comprises a distinct facial phenotype, macrodontia, short stature, and skeletal anomalies. So far, it has been reported in 29 individuals. Recently, diagnostic criteria were outlined. Here, we describe eight new patients whose clinical and radiological findings fit the diagnostic criteria of KBG syndrome. While most patients were sporadic in occurrence, in two families the disorder was transmitted from mildly affected mothers to their affected children. The phenotype of KBG syndrome has been reviewed based on published and present patients. EEG anomalies with or without seizures, mixed hearing loss, palatal anomalies with secondary speech disorder, distinct age-related behavior, and cryptorchidism are possible additional characteristics. Less common manisfestations were posterior fossa malformations, eye defects, and congenital heart defects.

Abnormalities, Multiple↗

PubMed2004

Ablepharon-macrostomia syndrome in a 46-year-old woman.

Ablepharon-macrostomia syndrome (AMS) is a rare condition reported to date in 13 patients worldwide. AMS is characterized by absent or short eyelids, absent eyebrows and eyelashes, macrostomia, and external ear abnormalities. Additional features include alopecia or sparse hair, hypoplastic malar region, redundant skin, rudimentary nipples, abnormal genitalia. While the AMS phenotype is well delineated in infants and children, clinical manifestations are rather poorly characterized in adulthood. Here, we report on an Italian woman who received a diagnosis of AMS at the age of 46 years after several surgical treatments. A clinical comparison between our patient and previously reported AMS cases aids in delineating the adult phenotype of AMS and further broadens the clinical spectrum of this condition.

Ear↗

PubMed2003

Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation.

Cerebello-oculo-renal syndromes (CORSs) and Joubert syndrome (JS) are clinically and genetically heterogeneous autosomal recessive syndromes that share a complex neuroradiological malformation resembling a molar tooth on brain axial images, a condition referred to as "molar tooth on imaging" (MTI) or the "molar tooth sign." The current literature on these syndromes is complex, with overlapping and incomplete phenotypes that complicate the selection of clinically homogeneous cases for genetic purposes. So far, only one locus (JBTS1 on 9q34) has been mapped, in two families with JS. Here, we describe a large consanguineous family with JS and nephronophthisis, representing a novel cerebello-renal phenotype. We have mapped this condition to the pericentromeric region of chromosome 11 and have named the locus "CORS2." The acronym "CORS" is proposed for all loci associated with JS, CORSs, and related phenotypes sharing the MTI, because this neuroradiological sign seems to be the unifying feature of these clinically heterogeneous syndromes.

Abnormalities, Multiple↗

PubMed2003

Familial blepharospasm is inherited as an autosomal dominant trait and relates to a novel unassigned gene.

Blepharospasm (BSP) is a common form of primary torsion dystonia (PTD). Although most cases are sporadic, an increased familial incidence of BSP has been reported. Precisely how blepharospasm is inherited remains unclear. We report on two Italian families with adult-onset focal BSP inherited as an autosomal dominant trait with reduced penetrance. None of the affected family members had the 3-bp (GAG) or the 18-bp deletion in the DYT1 gene. In one family, linkage analysis allowed us to exclude segregation of the disease with the known PTD loci (DYT1, DYT6, DYT7, and DYT13). These findings suggest that primary familial adult-onset BSP is a distinct entity among inherited PTD and is caused by a novel, unmapped gene.

Adolescent↗

PubMed2003

Analysis of the epsilon-sarcoglycan gene in familial and sporadic myoclonus-dystonia: evidence for genetic heterogeneity.

The epsilon-sarcoglycan gene (SGCE) on human chromosome 7q21 has been reported to be a major locus for inherited myoclonus-dystonia. Linkage to the SGCE locus has been detected in the majority of families tested, and mutations in the coding region have been found recently in families with autosomal dominant myoclonus-dystonia. To evaluate the relevance of SGCE in myoclonus-dystonia, we sequenced the entire coding region of the epsilon-sarcoglycan gene in 16 patients with either sporadic or familial myoclonus-dystonia. No mutations were found. This study suggests that epsilon-sarcoglycan does not play an important role in sporadic myoclonus-dystonia and supports genetic heterogeneity in familial cases.

Adolescent↗

PubMed2003

Recurrent triploidy of maternal origin.

Triploidy is the most frequent chromosome aberration in first trimester spontaneous abortions. In contrast to aneuploidies due to nondisjunction, increased maternal age is not a risk factor and the mechanism of triploidy remains poorly understood. To date, recurrence of triploidy of maternal origin has been described only in a few families suggesting some underlying genetic factors. Here, we report on a woman who underwent three consecutive triploid pregnancies, in two of which maternal origin of triploidy was proved by molecular analysis.

Abortion, Habitual↗