A Recurrent Intragenic Deletion in the Desmoglein 4 Gene Underlies Localized Autosomal Recessive Hypotrichosis

6 páginas, 2 figuras.A newly defined form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903), was recently described in the literature (Kljuic et al. 2003a; Rafique et al. 2003) and shown to be linked to chromosome 18. We identified a large, intragenic deletion in the desmoglein 4 gene (DSG4) as the underlying mutation in two unrelated families of Pakistani origin (Kljuic et al. 2003a). LAH is an autosomal recessive form of hypotrichosis affecting the scalp, trunk, and extremities, and largely sparing the facial, pubic, and axillary hair. Typical hairs are fragile and break easily, leaving short sparse scalp hairs with a characteristic appearance. Using comparative genomics, we also demonstrated that human LAH is allelic with the lanceolate hair (lah) mouse (Kljuic et al. 2003a), as well as the lanceolate hair (lah) rat phenotype (Jahoda et al. 2004). In order to expand the series of allelic mutations in the desmoglein 4 gene underlying LAH in humans, we begin molecular analysis of DSG4 in families from around the world. Here, we describe the study of a family of Pakistani origin with two siblings affected with LAH (Figure 1).This study was supported in part by grants USPHS NIH R01-AR44924 and the March of Dimes Birth Defects Foundation (A. M. C.).Peer reviewe

Mutation prevalence of cerebral cavernous malformation genes in Spanish patients

[Objective] To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients.[Methods] We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing.[Results] A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported.[Conclusions] Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.This work has been supported by grants CP10/00526 (Instituto de Salud Carlos III, Spain) and P07-CVI-02790 (Junta de Andalucía, Spain). RM received a fellowship of José Luis Castaño Foundation.Peer Reviewe

Clinical and molecular study of the extracellular matrix protein 1 gene in a spanish family with lipoid proteinosis

[Background] Lipoid proteinosis (LP) is a rare autosomal recessive disorder characterized by a hoarse voice, variable scarring, and infiltration of the skin and mucosa. This disease is associated with mutations of the gene encoding extracellular matrix protein 1 (ECM1). [Case Report]This was a clinical and molecular study of a new case of LP with a severe phenotype. A 35-year-old female born to nonconsanguineous parents developed dermatological and extracutaneous symptoms in her 9th month of life. The neurological abnormalities of the disease began to appear at the age of 19 years. Computed tomography revealed cranial calcifications. [Conclusions]The diagnosis of LP was confirmed by histopathological findings and direct sequencing of ECM1. A new homozygous nonsense mutation was identified in exon 7 of ECM1, c.1076G>A (p.Trp359*). This mutation was not detected in 106 chromosomes of healthy individuals with a similar demographic origin. Microsatellite markers around ECM1 were used to construct the haplotype in both the parents and the patient. Reports on genotype-phenotype correlations in LP point to a milder phenotype in carriers of missense mutations in the Ecm1a isoform, whereas mutations in the Ecm1b isoform are thought to be associated with more severe phenotypes. The present findings in a Spanish patient carrying a truncating mutation in exon 7 revealed complete dermatological and neurological manifestations. © 2014 Korean Neurological Association.The authors thank the patient and her family for their participation, and the financial support of grants from MICINN (no. SAF2007-60508) and Consejería de Ciencia Junta de Andalucía (no. CVI02790).Peer Reviewe

Mutation Prevalence of Cerebral Cavernous Malformation Genes in Spanish Patients

Objective: To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. Methods: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. Results: A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. Conclusions: Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.Instituto de Salud Carlos III CP10/00526Junta de Andalucía P07-CVI-02790Fundación José Luis Castañ

Neurexin and neuroligin genes in Alzheimer's disease

Póster presentado en la 11th International Conference on Alzheimer's & Parkinson's Diseases, celebrada en Florencia del 6 al 10 de marzo de 2013.-- Alzheimers Disease Neuroimaging Inititive[Objectives] The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD.[Methods] To explore this hypothesis we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1256 SNPs in the NRXN1, NRXN2, NRXN3 and NLGN1 genes (3009 cases and 3006 control individuals) using PLINK software.[Results] We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however the statistical significance obtained did not resist multiple testing corrections (OR=0.851, p=0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A replication study with SNP rs17757879 in a Spanish population (1785 cases and 1634 controls) confirmed this observation (OR=0.752, C.I.=0.570-0.991, p=0.042).[Conclusions] We conclude that NRXN3 might have a role in susceptibility to AD in males (rs17757879, OR=0.742, 95% C.I.=0.632-0.872, p=0.00028, final meta-analysis).Peer Reviewe

Genetic study of neurexin and neuroligin genes in Alzheimer's disease

The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males.Peer Reviewe

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Basic principles of Genetics

68 páginas, 10 figuras. 1º ed.Genetic disease may be caused by defects in one gene (Mendelian or monogenic diseases) or more than one gene (polygenic diseases), but it can also be a result of the interaction of environmental and genetic factors (complex or multifactorial traits) The major Mendelian patterns of inheritance are autosomal recessive (e.g. oculocutaneous albinism), autosomal dominant (e.g. Darier disease), X-linked recessive (e.g. hypohidrotic ectodermal dysplasia), and X-linked dominant (e.g. incontinentia pigmenti). Factors modifying the basic Mendelian pattern of inheritance include incomplete penetrance, age-dependent penetrance, variable expression, de novo mutations, pseudodominant inheritance, genomic imprinting, and mitochondrial inheritance. Chromosomal anomalies can consist of abnormalities in the number (e.g. polyploidy, aneuploidy) or in the structure (e.g. translocations, …)Peer reviewe

Epidemiología y genética de las convulsiones febriles

29 páginas, figuras.Peer reviewe