Novel mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1) and description of five ancestral haplotypes in patients with Mal de Meleda.

Mal de Meleda is a recessive, transgressive palmoplantar keratoderma for which we previously identified mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1). In this report we describe two new mutations: (i) a founder mutation, which changes a conserved cysteine residue to tyrosine (C99Y) in a large inbred Tunisian pedigree, and (ii) a signal sequence mutation (W15R), which was homozygous in a German family and heterozygous in a Scottish patient. Four ancestral haplotypes were observed in 69 patients from countries around the Mediterranean basin, and an additional haplotype was found in the German and Scottish patients.

No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 18q21.1.

A recent genome-wide scan showed strong evidence for a major locus for common syndromes of idiopathic generalized epilepsy (IGE) at the marker D18S474 on chromosome 18q21.1 (LOD score 4.5/5.2 multipoint/two-point). The present replication study tested the presence of an IGE locus in the chromosomal region 18q21.1. Our linkage study included 130 multiplex families of probands with common IGE syndromes. Eleven microsatellite polymorphisms encompassing a candidate region of 30 cM on either side of the marker D18S474 were genotyped. The two-point homogeneity LOD score for D18S474 showed strong evidence against linkage at the original linkage peak (Z = -18.86 at theta(m = f) = 0.05), assuming a recessive mode of inheritance with 50% penetrance. Multipoint parametric heterogeneity LOD scores < -2 were obtained along the candidate region when proportions of linked families greater than 35% were assumed under recessive inheritance. Furthermore, non-parametric multipoint linkage analyses showed no hint of linkage throughout the candidate region (P > 0.19). Accordingly, we failed to support evidence for a major IGE locus in the chromosomal region 18p11-18q23. If there is a susceptibility locus for IGE in this region then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Infantile convulsions and paroxysmal choreoathetosis in a consanguineous family.

Infantile convulsions and paroxysmal choreoathetosis is a rare autosomal-dominant disorder characterized by variable presentation of benign infantile seizures and paroxysmal dyskinesia. The disease gene was mapped to chromosome 16p12-q12. We report a consanguineous Turkish family with three individuals affected by infantile convulsions and paroxysmal choreoathetosis. Two siblings whose parents were first cousins had benign infantile convulsions and paroxysmal choreoathetosis. Whereas their father presented only paroxysmal choreoathetosis. The siblings displayed an earlier age of onset and increased frequency of the paroxysmal symptoms than their father. We genotyped the pedigree with polymorphic microsatellite markers, spanning the pericentromeric region of chromosome 16. Construction of the haplotypes demonstrated the segregation of the disease with the infantile convulsions and paroxysmal choreoathetosis locus. The disease was inherited as an autosomal-dominant trait with incomplete penetrance. The affected father was heterozygous for the disease haplotype. However, the two affected siblings manifested homozygosity for the disease haplotype. By haplotype analysis, we confirmed the assignment of the locus for infantile convulsions and paroxysmal choreoathetosis to chromosome 16p12-q12 in this family, and our results also demonstrate that homozygotes for infantile convulsions and paroxysmal choreoathetosis may have a more severe form of the disease than heterozygotes.

Physicians' response to a letter to confirm diagnosis in a genetic study of psoriasis.

Context. Phenotyping of diseases is essential for genetic studies. In common diseases like psoriasis, the co-operation of family practitioners is helpful to confirm the phenotype of the patients. A genetic study was initiated in France by Généthon in 1996 in order to localise and identify genes for susceptibility to psoriasis. We used an unusual means to confirm psoriasis diagnosis: letters sent to patients' practitioners. Objective. To evaluate the efficiency of this means, and analyse the factors influencing the response rate of patients' physicians to a letter designed to confirm a diagnosis of psoriasis. Design. In the cases of putative psoriasis diagnosis (evaluated by systematic phone calls to the patients by a dermatologist), and with the agreement of the patients, a letter was sent to the patient's referent physician. We evaluated response rate to the letter. Results. 533 letters concerning 762 patients were sent to 456 physicians. The global response rate was 56.5%. The characteristics which modified the response rate were: the quality of the letter sent and some physicians' characteristics: dermatologists versus GPs, hospital versus private practice, and size of the town in which the physician had his practice. Conclusions. The use of letters to physicians as a means of phenotyping patients' diseases is an efficient method of confirming clinical diagnosis and should be used more frequently to confirm clinical diagnosis in large genetic studies. Some parameters such as ease of reply to the letter, whether the physician was a GP or a specialist, and the type of practice increased the response rate.

An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders.

Psoriasis is a common inflammatory and hyperproliferative skin disease. Recent studies have reported that common genetic factors may underlie both skin and immune-mediated disorders. We hypothesized that such genes may be involved in susceptibility to psoriasis, and undertook an association analysis of 22 candidate genes in a set of French high-risk psoriasis families. One hundred fifty-three single-nucleotide polymorphisms (SNPs) were genotyped and the transmission of alleles in nuclear families was analyzed using the FBAT (family-based association test). To further investigate suggestive associations, LNM (logistic-normal models) and MQLS (modified quasi-likelihood score) methods, which take the whole pedigree structure information of families into consideration, were also applied. Our study supported the involvement of six candidate genes in susceptibility to psoriasis: SCL12A8, which belongs to the solute carrier gene family; FLG and TGM5, which are involved in epidermal differentiation; CARD15 and CYLD, which modulate the transcription factor NF-kB; and IL1RN, which encodes an IL receptor antagonist. Furthermore, we found evidence for interaction between the major risk allele, HLA-Cw6, and CARD15, CYLD, and TGM5 susceptibility alleles. Taken together, our data show that shared genetic factors may contribute to the etiology of both psoriasis and other skin or immune-mediated disorders.

ADAM33, a new candidate for psoriasis susceptibility.

Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT) for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations). This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.

Confirmation of psoriasis susceptibility loci on chromosome 6p21 and 20p13 in French families.

Plaque psoriasis is a chronic inflammatory disorder of the skin. It is inherited as a multifactorial trait, with a strong genetic component. Linkage studies have identified a large number of disease loci, but very few could be replicated in independent family sets. In this study, we present the results of a genome-wide scan carried out in 14 French extended families. Candidate regions were then tested in a second set of 32 families. Analysis of the pooled samples confirmed linkage to chromosomes 6p21 (Z(MLB) score=3.5, P=0.0002) and 20p13 (Z(MLB) score=2.9, P=0.002), although there was little contribution of the second family set to the 20p13 linkage signal. Moreover, we identified four additional loci potentially linked to psoriasis. The major histocompatibility complex region on 6p21 is a major susceptibility locus, referred to as PSORS1, which has been found in most of the studies published to date. The 20p13 locus segregates independently of PSORS1 in psoriasis families. It has previously been thought to be involved in the predisposition to psoriasis and other inflammatory disorders such as atopic dermatitis (AD) and asthma. Although psoriasis and AD rarely occur together, this reinforces the hypothesis that psoriasis is influenced by genes with general effects on inflammation and immunity.

Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3.

We report the identification of mutations in a non-syndromic autosomal recessive congenital ichthyosis (ARCI) in a new gene mapping within a previously identified locus on chromosome 19p12-q12, which has been defined as LI3 in the OMIM database (MIM 604777). The phenotype usually presents as lamellar ichthyosis and hyperlinearity of palms and soles. Seven homozygous mutations including five missense mutations and two deletions were identified in a new gene, FLJ39501, on chromosome 19p12 in 21 patients from 12 consanguineous families from Algeria, France, Italy and Lebanon. FLJ39501 encodes a protein which was found to be a cytochrome P450, family 4, subfamily F, polypeptide 2 homolog of the leukotriene B4-omega-hydroxylase (CYP4F2) and could catalyze the 20-hydroxylation of trioxilin A3 from the 12(R)-lipoxygenase pathway. Further oxidation of this substrate by the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex, in which one component, ALDH3A2, is known to be mutated in Sjögren-Larsson syndrome (characterized by ichthyosis and spastic paraplegia), would lead to 20-carboxy-(R)-trioxilin A3. This compound could be involved in skin hydration and would be the essential missing product in most forms of ARCI. Its chiral homolog, 20-carboxy-(S)-trioxilin A3, could be implicated in spastic paraplegia and in the maintenance of neuronal integrity.

Exploration of the genetic architecture of idiopathic generalized epilepsies.

PURPOSE: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. METHODS: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. RESULTS: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. CONCLUSIONS: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.

Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families.

PURPOSE: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis. METHODS: Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models. RESULTS: Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity. CONCLUSIONS: Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.

A locus for simple pure febrile seizures maps to chromosome 6q22-q24.

Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity. We report a clinical and genetic study of three families with simple FS segregating as an autosomal dominant (AD) trait with high penetrance. All affected members presented a homogeneous phenotype of simple FS. The FS ceased before the age of 5 years. Among the 29 affected family members, only one patient presented two afebrile seizures, and none of the others developed concomitant or subsequent epilepsy. The phenotype differs from that previously reported in families presenting FS or generalized epilepsy with febrile seizures plus (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a genome-wide scan in the largest family. It led to the identification of a new locus on chromosome 6q22-q24 spanning 6.4 cM between D6S1620 and D6S975. For one of the other two families, the trait also segregated with this locus, but linkage studies could not restrict the candidate region further. The absence of linkage in the third family supports genetic heterogeneity of the AD form of pure simple FS. Sequence analysis excluded the implication of five candidate genes [A kinase anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)] in the interval based on function. The locus mapping to 6q22-q24 seems to be the first identified locus responsible for pure simple FS, the most frequent form of FS. Studies are ongoing to identify the gene.

Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis.

We report the genomic localization by homozygosity mapping and the identification of a gene for a new form of non-syndromic autosomal recessive congenital ichthyosis. The phenotype usually presents as non-bullous congenital ichthyosiform erythroderma with fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. A few patients presented a more generalized lamellar ichthyosis. Palmoplantar keratoderma was present in all cases, whereas only 60% of the patients were born as collodion babies. Six homozygous mutations including one nonsense and five missense mutations were identified in a new gene, ichthyin, on chromosome 5q33 in 23 patients from 14 consanguineous families from Algeria, Colombia, Syria and Turkey. Ichthyin encodes a protein with several transmembrane domains which belongs to a new family of proteins of unknown function localized in the plasma membrane (PFAM: DUF803), with homologies to both transporters and G-protein coupled receptors. This family includes NIPA1, in which a mutation was recently described in a dominant form of spastic paraplegia (SPG6). We propose that ichthyin and NIPA1 are membrane receptors for ligands (trioxilins A3 and B3) from the hepoxilin pathway.

Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome.

Kindler syndrome is a rare autosomal-recessive genodermatosis characterized by bullous poikiloderma with photosensitivity. We report the localization to chromosome 20p12.3 by homozygosity mapping and the identification of a new gene, which we propose to name kindlerin. We found four different homozygous mutations in four consanguineous families from North Africa and Senegal; three are expected to lead to premature stop codons and truncated proteins and the fourth involves a splice site. We were unable to identify a mutation in kindlerin in a fifth consanguineous family from Algeria with a similar phenotype and in which the patient was homozygous for the markers in the 20p12.3 interval. The kindlerin protein contains several domains which are shared by a diverse group of peripheral membrane proteins that function as membrane-cytoskeleton linkers: two regions homologous to band 4.1 domain of which one includes a FERM domain with a NPKY sequence motif, and a third region with a PH or pleckstrin homology domain. Kindlerin might be involved in the bidirectional signaling between integrin molecules in the membrane and the cytoskeleton, and could be involved in cell adhesion processes via integrin signaling.

Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.

We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway.

L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.

l-2-Hydroxyglutaric aciduria (l-2-HGA) is characterized by progressive deterioration of central nervous system function including epilepsy and macrocephaly in 50% of cases, and elevated levels of l-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid (CSF). Nuclear magnetic resonance imaging shows distinct abnormalities. We report the identification of a gene for l-2-HGA aciduria (MIM 236792) using homozygosity mapping. Nine homozygous mutations including three missense mutations, two nonsense mutations, two splice site mutations and two deletions were identified in the gene C14orf160, localized on chromosome 14q22.1, in 21 patients from one non-consanguineous and 14 consanguineous Turkish families. We propose to name the gene duranin. Duranin encodes a putative mitochondrial protein with homology to FAD-dependent oxidoreductases. The functional role of this enzyme in intermediary metabolism in humans remains to be established.

Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.

Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been localized on chromosome 2q33-35. We report the identification of five missense mutations in the ABCA12 gene in nine families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one non-consanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intracellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in cellular lipid trafficking in keratinocytes.

Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12.

PURPOSE: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12. METHODS: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years. RESULTS: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups. CONCLUSIONS: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.