Total anonychia congenita in a woman with normal intelligence: report of a further case.
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Congenital Abnormalities↗
Biomedical subjects
M Seri
Publications and source records attributed to M Seri.
Dynamics of the reactivity to MBP in multiple sclerosis.
Though many lines of evidence support the importance of myelin basic protein (MBP) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), its role in multiple sclerosis (MS) is still debated as well as the significance of epitope spreading in disease progression. We characterised the response to MBP in eight MS subjects and three of these were followed over time. In one case, the follow up lasted over a 6-year period. Clonal expansion, clonal persistence and epitope spreading against other MBP determinants was detected irrespective of disease course. In one patient we identified a novel T-cell receptor variable gene (BV28S2) which may be involved in the selection of MBP determinants, as suggested by experiments performed in the presence of mismatched antigen presenting cells (APC) between two subjects compatible for HLA-DR2 subtype but differing for the epitope recognised. Our findings do not sustain a role for the response to MBP effecting on clinical course and suggest that a novel TCR gene may be involved in the recognition of unusual self antigens.
Amino Acid Sequence↗
Congenital hypoplastic anaemia in a patient with a new multiple congenital anomalies-mental retardation syndrome.
We report on a girl with congenital hypoplastic anaemia, "coarse" face, generalized hypertrichosis with scalp hypotrichosis, short fifth finger, hypoplastic toenails, and mental retardation. A sister of the proposita, who died at the age of 1 year, had severe congenital anaemia, hypoplastic fingernails, low birth weight, failure to thrive, and repeated upper respiratory tract infections. Based on family history, we suspect that hypoplastic anaemia and the same multiple congenital anomalies-mental retardation syndrome (MCA/MR) were also present in this sister. To the best of our knowledge, this patient represents the first report of congenital hypoplastic anaemia and such a complex MCA/MR syndrome, probably inherited as an autosomal recessive trait.
Abnormalities, Multiple↗
KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs.
We describe the identification and characterization of a new gene deleted in the AMME contiguous gene syndrome. This gene is predominantly expressed in heart, skeletal muscle, spinal cord, and brain. Screening of placenta and NT2 cDNA libraries enabled us to obtain the 1.5-kb full-length transcript, which shows a 426-bp open reading frame. Since the resulting 142-amino-acid peptide has a single putative transmembrane domain and a weak but suggestive homology with KCNE1 (minK), a protein associated with the KCNQ1 potassium channel (KVLQT1), we named this new gene KCNE1-like (KCNE1L). To obtain greater insight into this new member of an apparently distinct protein family, we have identified and characterized the homologous mouse gene (Kcne1l), which encodes a peptide of 143 amino acids with 91% homology and 80% identity. The expression pattern of mouse Kcne1l in the developing embryo revealed strong signal in ganglia, in the migrating neural crest cells of cranial nerves, in the somites, and in the myoepicardial layer of the heart. The specific distribution in adult tissues, the putative channel function, and the expression pp6tern in the developing mouse embryo suggest that KCNE1L could be involved in the development of the cardiac abnormalities as well as of some neurological signs observed in patients with AMME contiguous gene syndrome.
Animals↗
Characterization of a murine gene homologous to the bovine CaCC chloride channel.
The bovine CaCC protein is a putative Ca2+-dependent Cl- channel of airway epithelial cells. Therefore, CaCC proteins could contribute to transepithelial Cl- transport and accordingly modify the phenotype of cystic fibrosis (CF) patients. We have identified a murine EST containing a full-length cDNA coding for a 902-amino-acid protein highly homologous to bovine CaCC. The murine gene (mCaCC) maps to chromosome 3 at the H2-H3 band and is expressed, as indicated by Northern blot analysis, in mouse skin and kidney but not in brain, heart, lung or testis. RT-PCR indicates a low expression in tracheal epithelial cells. Heterologous expression of mCaCC in Xenopus oocytes elicits membrane currents that are anion-selective and inhibited by DIDS and by niflumic acid, a blocker of the endogenous chloride current in oocytes. The identification of genes belonging to the CaCC family will help to evaluate their role as ion channels or channel regulators and their actual contribution to epithelial chloride transport.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Autosomal dominant aplasia cutis congenita: report of a large Italian family and no hint for candidate chromosomal regions.
We studied a three-generation pedigree in which seven individuals were affected by aplasia cutis congenita, a rare disorder characterized by the congenital absence of the epidermis, dermis and subcutaneous tissue of the vertex or occipital region. Accurate clinical and formal genetic analysis suggested that this family was affected by the autosomal dominant form of the disease, a hereditary condition due to mutations of an unknown gene. To define the map position of this locus, we performed linkage analysis on candidate chromosomes (long arm of chromosomes 1 and 12). Negative lod scores were obtained for all markers analysed and linkage with genes located in these chromosomal regions was excluded.
Chromosome Mapping↗
Exclusion of the Sonic Hedgehog gene as responsible for Currarino syndrome and anorectal malformations with sacral hypodevelopment.
Anorectal malformations (ARMs) are common congenital anomalies that account for 1:4 digestive malformations. ARM patients show different degrees of sacral hypodevelopment while the hemisacrum is characteristic of the Currarino syndrome (CS). Cases of CS present an association of ARM, hemisacrum and presacral mass. A gene responsible for CS has recently been mapped in 7q36. Among the genes localized in this critical region, sonic hedgehog (SHH) was thought to represent a candidate gene for CS as well as for ARM with different levels of sacral hypodevelopment according to its role in the differentiation of midline mesoderm. By linkage analysis we confirmed the critical region in one large family with recurrence of CS. In addition, the screening of SHH in 7 CS and in 15 sporadic ARM patients with sacral hypodevelopment allowed us to exclude its role in the pathogenesis of these disorders.
Anal Canal↗
SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.
X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency to Epstein-Barr virus (EBV). The gene responsible for XLP has recently been identified as the four-exon SH2D1A gene encoding a 128-amino-acid protein that contains an SH2-domain. Functional studies indicate the SH2D1A protein acts as a regulator of at least two signal transduction pathways initiated by the cell surface molecules SLAM and 2B4, respectively, and possibly related to the host immune response to EBV infection. We have carried out a systematic mutation study of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and have reconstructed the haplotypes of the patients. Four out of the 13 mutations detected are previously unreported. The identification of SH2D1A mutations in carriers from all three XLP families screened and the detection of mutations in two out of eight atypical patients indicates the usefulness of a DNA-based diagnosis for XLP disease.
Carrier Proteins↗
Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.
Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.
Child↗
Lower extremity counterpart of the Poland syndrome.
Below-the-knee right leg hypoplasia and ipsilateral toe brachysyndactyly were observed in a 4-year-old female with an otherwise normal phenotype. Electromyographic and nerve conduction studies were normal. The Doppler evaluation was consistent with a 50% reduction in the blood supply from the femoral artery, suggesting vascular disruption as the pathogenic mechanism. Our observations support the hypothesis that a lower extremity counterpart of the Poland syndrome does exist and that the extent of limb involvement is dependent on the level of vascular disruption.
Child, Preschool↗
Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy.
We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.
Abnormalities, Multiple↗
Identification of LMX1B gene point mutations in italian patients affected with Nail-Patella syndrome.
Nail-Patella syndrome, or osteo-onychodysplasia, is an autosomal dominant disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns and nephropathy. Previous studies have demonstrated linkage of the Nail-Patella locus with polymorphic markers on human chromosome 9q34. Recently, point mutations in the LMX1B gene have been identified in Nail-Patella patients and in families with recurrence of Nail-Patella syndrome and open-angle glaucoma. We describe here the identification of additional point mutations in the LMX1B gene in a set of Italian patients affected with Nail-Patella syndrome: two deletions of 1 and 2 bp causing a frameshift in two sporadic patients and nonsense mutations in two familial and one sporadic cases have been identified. All the mutations affect the homeodomain of the LMX1B protein and could cause the Nail-Patella syndrome through a loss of function as well as a dominant negative effect. Haplotype analysis in the two familial cases carrying the same stop codon mutation suggests the presence of a founder effect. Finally, analysis of cDNA clones obtained from human fetal kidney has revealed the existence of two different transcripts of LMX1B gene likely due to an alternative splicing.
Alternative Splicing↗
A method for point mutation analysis that links SSCP and dye primer fluorescent sequencing.
A method is presented for mutation detection directly from single-strand conformational polymorphism (SSCP) variants. This approach is based on: (i) amplification of the exons to be analysed by SSCP using the forward primer with an eight-base tail to form a universal SSCP cassette; (ii) excision from the gel of the shifted silver-stained bands; (iii) reamplification of the eluted DNAs using, as the forward primer, a 26-base universal adaptor primer corresponding to the 18-base-21M13 sequence plus the eight nucleotides of the universal SSCP cassette; and (iv) direct sequencing of the purified products using the standard-21M13 fluorescent primer. This procedure presents several advantages including the avoidance of a cloning step which leads to significant time reduction, while maintaining comparable accuracy at relatively low costs. In conclusion, the presence of the universal SSCP cassette and subsequent reamplification with the same adaptor primer for direct sequencing makes the method universal for scanning and identification of gene alterations.
Base Sequence↗
Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary antigens) or for PPD and tetanus toxoid (secondary antigens)
Antigen derived peptides bound on MHC class II molecules on presenting cells stimulate specific CD4 lymphocytes that are in a naive state if antigen is given for the first time, or in a memory state if antigen has been previously encountered. In order to compare clonal heterogeneity of the human CD4+ T helper repertoire in primary vs. recall responses, we have generated T cell lines in vitro by repeated stimulation of peripheral lymphocytes with primary or with recall antigens. Clonal heterogeneity was broad in the case of recall response to tetanus toxoid or PPD, with a high frequency of specific precursors (> 100 cells/10(6) lymphocytes). In contrast, T cell lines responsive to primary antigens (HIV gp120 or HIV p66) were oligoclonal as defined by TCR V beta gene usage and by spectratyping, and the precursor frequency was low (< 2 cells/10(6) lymphocytes). Primary T cell lines generated from blood samples drawn at different times from the same donor showed that clones with identical TCR CDR3 region coding sequences were expanded, suggesting that in these individuals a large progeny derived from one single precursor is present, even though a previous encounter with the antigen was not documented. Assuming an even in vivo distribution of such cells, the presence of one precursor every 10(6) CD4 lymphocytes (within the CD4 T repertoire that comprises roughly 10(11) CD4 T cells) indicates that approximately 10(5) identical T cells from the same clonal precursor account for the primary response against the model antigens we have studied.
Amino Acid Sequence↗
Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.
Antigens, CD↗
Association of multiple endocrine neoplasia type 2 and Hirschsprung disease.
In a few patients with Hirschsprung disease (HSCR) and no clinical symptoms of multiple endocrine neoplasia type 2 (MEN-2A) or medullary thyroid carcinoma (MTC), missense mutations in the cysteine residues 609 and 620 of the Ret gene have been identified. In several pedigrees with either MEN-2A or familial MTC (FMTC) a documented germline mutation in cysteine 618 or 620 follows the segregation of the disease phenotype. The appearance of the HSCR phenotype in such patients and pedigrees cannot be easily reconciled with the gain of function which is associated with the dominant oncogenic effect of MEN-2A mutations. Gastrointestinal manifestations are known to occur also in association with MEN-2B but, to the best of our knowledge, in only very few cases the intestinal phenotype of MEN-2B has been investigated by enzymo-histochemical techniques, as in the present work. We report an extensive molecular study of patients, two with HSCR and FMTC carrying a Cys620Arg or Ser mutation and two with MEN-2B and gastrointestinal symptoms carrying a Met918Thr mutation. One of the latter two patients showed aganglionosis of the last 5 cm of rectum which caused a congenital megacolon leading to the diagnosis and operation for HSCR. The mutation screening of all the exons of Ret in 3 of these patients did not reveal any additional mutation. Therefore these results do not support the hypothesis of additional constitutional Ret mutations in patients showing association of MEN-2 and HSCR, whilst the histochemical and clinical data in one of these patients indicate that MEN-2B can be associated with a true form of short segment HSCR.
Drosophila Proteins↗
Ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum: variable expression of a single syndrome?
We present two unrelated children, a male and a female, with signs of ectodermal dysplasia, mental retardation, agenesis/ dysgenesis of the corpus callosum, and primary hypothyroidism. Reports of ectodermal dysplasia with CNS malformations or hypothyroidism or both are rare. We suggest that the condition we describe is a distinct entity within the large group of ectodermal dysplasia syndromes and that it has a variable clinical spectrum. As both males and females are affected and in a few reports some parents show minimal signs, the inheritance is likely to be autosomal dominant.
Agenesis of Corpus Callosum↗
Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM *240300, also called APS 1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is generally characterized by two of the three major clinical symptoms that may be present, Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have a number of other clinical symptoms including chronic gastritis, gonadal failure, and rarely, autoimmune thyroid disease and insulin-dependent diabetes mellitus. We and others have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes, and fetal liver and encodes a protein containing motifs suggestive of a transcriptional regulator, including two zinc finger motifs (PHD finger), a proline-rich region, and three LXXLL motifs. Six mutations, in cluding R257X, the predominant Finnish APECED allele, have been defined. R257X was also observed in non-Finnish APECED patients occurring on different chromosomal haplotypes suggesting different mutational origins. Here we present mutation analyses in an extended series of patients, mainly of Northern Italian origin. We have detected 12 polymorphisms, including one amino acid substitution, and two additional mutations, R203X and X546C, in addition to the previously described mutations, R257X, 1096-1097insCCTG, and a 13-bp deletion (1094-1106del). R257X was also the common mutation in the Northern Italian patients (10 of 18 alleles), and 1094-1106del accounted for 5 of 18 Northern Italian alleles. Both R257X and 1094-1106del were both observed in patients of four different geo-ethnic origins, and both were associated with multiple different haplotypes using closely flanking polymorphic markers showing likely multiple mutation events (six and four, respectively). The identification of common AIRE mutations in different APECED patient groups will facilitate its genetic diagnosis. In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system.
Female↗