Patrizia Lulli

HLA-DQ and risk gradient for celiac disease.

Celiac disease (CD) is a rare example of multifactorial disorder in which a genetic test is of great clinical relevance, as the disease rarely develops in the absence of specific HLA alleles. We typed DR-DQ genes in 437 Italian children with celiac disease, 834 first-degree relatives, and 551 controls. Of patients, 91% carried DQ2 and/or DQ8 heterodimers, 6% only had beta2 chain, 2% was alpha5 positive, and four were DQ2/DQ8/beta2/alpha5 negative. Only the presence of alpha5 resulted negatively associated to disease (p = 2 x 10(-4)), whereas we confirmed the effect of the beta half of DQ2 dimer on CD predisposition (p = 4 x 10(-12)). Considering 1:100 disease prevalence, we obtained a risk gradient ranging from 1:7 for DQ2 and DQ8 individuals down to 1:2518 for subjects lacking all predisposing factors. The DQB1*02 and DQB1*0302 concurrence (p = 9 x 10(-4)), besides the DQB1*02/*02 homozygosity, had an additional role in disease genetic determination. The CD prevalence rose to 17.6% in sisters, 10.8% in brothers, and 3.4% in parents. In the three groups, the subjects carrying high-risk HLA molecules were 57%, 71%, and 58%; among them, 29%, 15%, and 6% respectively had CD. Those siblings and parents with no susceptible factors were not affected. These findings indicate the impact of the HLA test for CD in clinical practice.

Tumor necrosis factor gene polymorphism in migraine

Objective.—To better define the involvement of human leukocyte antigen region (HLA) genes in migraine via an association study of the tumor necrosis factor (TNF) genes, located in the HLA class III region, with migraine with and without aura.

HLA-LINKED SPINOCEREBELLAR ATAXIA - A CLINICAL AND GENETIC-STUDY OF LARGE ITALIAN KINDREDS

Five families with late onset autosomal dominant spinocerebellar ataxia, were studied. Linkage between the disease and HLA loci on the short arm of chromosome 6 was shown in the two largest pedigrees. Clinical study of 26 patients and neuropathological study in one are reported. The disease was characterized by cerebellar and pyramidal involvement variably associated with cranial nerve and peripheral nervous system disorders. A remarkable concordance of the main clinical features was observed in patients with similar disease duration. Comparison with previous reports of HLA‐linked spinocerebellar ataxia kindreds showed differences in clinical phenotypes. Although these might be due to genetic variation, the hypothesis is suggested that the phenotype might appear more homogeneous if disease duration is taken into account.

Genetics of migraine and pharmacogenomics: some considerations

Migraine is a complex disorder caused by a combination of genetic and environmental factors.Although family and twin studies show that there is a genetic component in migraine, no genes predisposing to common forms of the disorder, migraine with and without aura, have been identified. Patients with migraine respond differently to a given drug administered. The efficacy of therapy and the occurrence of adverse drug response are a consequence of individual variability. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. The development of International Hap Map project could provide a powerful tool for identification of the candidate genes in this complex disease and pharmacogenomics research could be the promise for individualized treatments and prevention of adverse drug response.

Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: Report of a novel mutation of the PCNT gene

We report on a 3‐year‐old boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome. Western blot analysis of the patients lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion (c.1527_1528insA) in exon 10 of the PCNT gene, which leads to a frameshift (Treo510fs) and to premature protein truncation. PCNT mutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested.

CHROMOSOME 6P-ENCODED HLA-DR2 DETERMINANT DISCRIMINATES MIGRAINE WITHOUT AURA FROM MIGRAINE WITH AURA

Segregation analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA) have multifactorial inheritance, but involved genetic and environmental factors are largely unknown. A controlled study was performed to assess the HLA-driven liability to migraine and to verify if the heterogeneity between MWoA and MWA is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood donors as controls, coming from the same geographic area, were studied. Tissue typing was performed using the standard complement-dependent microlymphocytotoxicity technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for HLA Class II. Data emerging from the present study showed no altered distribution for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared to the control group. HLA Class II DR2 antigen showed a decreased frequency in MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039, RR = 0.21). These results seem to support the hypothesis of a protective role of DR2 antigen in MWA and provide additional basis for the proposed difference within MWoA and MWA.

HLA Antigens and Aging

The major histocompatibility complex is one of the gene systems that influence aging.’ Although it is well known that HLA antigens in man are closely related to autoimmune diseases as well as to immunoresponsiveness, it is not yet clear if a relation exists between HLA antigens and longe~i ty .~ .~ As extreme longevity may be influenced by environmental factors as well as genetic background, we typed for HLA antigens a series of persons over 95 years of age assuming that, although lifestyle, diet, and hygiene can influence life span up to a certain age, genetic factors could predispose to longevity in persons living longer than 95 years.

HLA-DRB1 and -DQB1 loci in three west African ethnic groups: Genetic relationship with sub-Saharan African and European populations

The Fulani of west Africa have been shown to be less susceptible to malaria and to mount a stronger immune response to malaria than sympatric ethnic groups. The analysis of HLA diversity is useful for the assessment of the genetic distance between the Fulani and sympatric populations, which represents the necessary theoretical background for the investigation of genetic determinants of susceptibility to malaria. We assessed the polymorphism of HLA-DRB1 and -DQB1 loci and analyzed the distribution of alleles/haplotypes in Fulani, Mossi, and Rimaibé from Burkina Faso. We then investigated the genetic relationship of these three ethnic groups with other sub-Saharan African populations as well as with Europeans. We confirmed that the Fulani from Burkina Faso are genetically distinct from sympatric Mossi and Rimaibé. Furthermore the Fulani from Burkina Faso are close to those from The Gambia and, intriguingly, share the distribution of specific alleles with east African populations (Amhara and Oromo). It is noteworthy that the HLA-DRB1*04 and -DQB1*02 alleles, which are implicated in the development of several autoimmune diseases, are present at high frequency in the Fulani, suggesting their potential involvement in the enhanced immune reactivity observed in this population.

DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: Fourteen novel ATM mutations

The gene for ataxia-telangiectasia (A-T:MIM: #208900), ATM, spans about 150 kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients.

HLA and Complement Factors Alleles Sharing in Italian Couples with Recurrent Spontaneous Abortions

Recurrent Spontaneous Abortion (RSA) is postulated to be due to several factors including immunogenetic mechanisms. Many studies have been conducted on the effect of the MHC region in the reproductive phenomena suggesting an immunological or genetic involvement in RSA. We studied couples with 3 or more abortions among a larger group of couples in which female partners were anti-cardiolipin antibodies negative, resulting in a population of 43 couples typed for HLA-A, B, C, DR, DQ. In 16 of these 43 couples, complement factors C4A, C4B, and Bf were typed. The data shows a statistically significant increase of C4B*Q0 in RSA patients (N = 32) compared with the control population (N = 44) (pc = .00147) and also a statistically significant increase of C4B*Q0 sharing in aborting couples (43.75%) against the expected sharing rate in the control population (1.86%) (p < .001). Frequency increase of C4B*Q0 allele in aborting population leads to the hypothesis that an imbalance of complement factors expression and activity can have detrimental effects on implantation and embryo survival. Additionally, the significant sharing rate of C4B*Q0 in couples with RSA could indicate the existence of a gene in linked to this allele predisposing to RSA and acting in a recessive manner if present in double copies in the fetus.