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PubMed2004

Homozygous splice site mutations in PKP1 result in loss of epidermal plakophilin 1 expression and underlie ectodermal dysplasia/skin fragility syndrome in two consanguineous families.

During the last years, a growing number of inherited skin disorders have been recognized to be caused by abnormal function of desmosomal proteins. In the present study, we describe the first female individuals affected with the ectodermal dysplasia/skin fragility syndrome (MIM604536), a rare autosomal recessive disease due to mutations in the PKP1 gene encoding plakophilin 1, a critical component of desmosomal plaque. One patient was shown to carry a homozygous splice site mutation in intron 4. The second patient displayed a homozygous recurrent mutation affecting the acceptor splice site of intron 1. Both mutations were associated with intraepidermal separation, widening of intercellular spaces, and abnormal desmosome ultrastructure, and were found to result in the absence of immunoreactive plakophilin 1 in the epidermis of the affected individuals. These two cases emphasize the role of molecular genetics in the assessment of congenital blistering in newborns and illustrate the importance of proper desmosomal activity for normal epidermis development and function.

Child, Preschool↗
PubMed2006

Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene.

Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.

Acidosis, Renal Tubular↗
PubMed2006

Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin.

Neuroectodermal syndromes involving the skin and inner ear may be associated with mutations in connexin proteins, which form gap junctions important for intercellular communication. Vohwinkel syndrome (keratodermia mutilans with hearing loss) and keratitis-ichthyosis-deafness (KID) syndrome are rare ectodermal dysplasias associated with dominant mutations in the GJB2 gene encoding connexin 26. We report here two patients, one with KID and one with Vohwinkel syndrome. Both displayed unusual clinical features and responded well to long-term treatment with oral retinoid. Mutation analysis revealed a novel GJB2 mutation p.Gly59Ser in the patient with Vohwinkel syndrome, whereas a recurrent mutation p.Asp50Asn was found in the patient with KID syndrome. The clinical features, particularly a proneness to skin cancer in the patient with Vohwinkel syndrome, are discussed in relation to the identified genotypes.

Acitretin↗
PubMed1989

Identification and characterization of nine RFLPs at the adenosine deaminase (ADA) locus.

We have identified and/or characterized at least nine RFLPs at the adenosine deaminase (ADA) locus, detected by digestion of DNA with MspI, BanII, PstI, BalI, and PvuII. The RFLPs were distributed over approximately 15 kb of the gene, from IVS 2 to IVS 10. They exhibited Mendelian inheritance and were in Hardy-Weinberg equilibrium. For seven fully characterized RFLPs, the gene frequencies of the rare alleles in 90 chromosomes examined ranged from .33 to .04, the PIC from .34 to .07, and the heterozygosity from .09 to .58. In kindreds examined (58 independent chromosomes), a total of nine haplotypes could be defined on the basis of seven fully characterized RFLPs with a heterozygosity of .62 and PIC of .53. Because there was considerable linkage disequilibrium, only three haplotypes accounted for 90% of individuals. Similar heterozygosity and PIC values (.59 and .51, respectively) could be obtained on the basis of haplotypes defined by the two sites that were the most polymorphic and that were in the least degree of linkage disequilibrium. A strategy for use of the RFLPs in linkage studies is suggested. We have also examined DNA from 17 patients with complete genetic deficiency of ADA (resulting in severe combined immunodeficiency [ADA-SCID] and from 10 patients with partial ADA deficiency (deficient in erythrocytes, with varying levels of ADA in other cells and normal immune function). Although the RFLPs detected genetic compounds among both types of patients, there was, as expected, a decreased incidence of heterozygosity (ADA-SCIDs, .29; partial ADA deficients, .20). Two additional haplotypes not found in the normal population were identified in homozygous form in patients. This information should be useful in developing a rational approach to delineation of mutations at the ADA locus as well as in distinguishing recurrent mutations of independent origin from those derived from a common progenitor.

Adenosine Deaminase↗
PubMedDate not supplied

[Junctional epidermolysis bullosa. Identification of a new mutation in two Lebanese families].

BACKGROUND: Junctional epidermolysis bullosa (JEB) represents a genetically heterozygous group of bullous disorders characterized by dermo-epidermal separation resulting from mutations affecting the main dermo-epidermal adhesion factor, laminin-5, its cellular receptor, integrin alpha6B4, or collagen XVII. We report the identification of a new mutation of LAMA3, encoding laminin-5 alpha3 subunit in two unrelated Lebanese families. PATIENTS AND METHODS: Two female newborn, descending from 1st degree consanguineous marriages, presented a lethal form of EBJ-Herlitz. Histologic, ultrastructural and immunofluorescence studies were performed in order to ascertain the diagnosis and to direct genetic analysis. Mutation search was conducted through direct DNA sequencing of patients and ascendants. RESULTS: Immunohistology of frozen skin samples revealed an extremely reduced immunoreactivity for the alpha3 laminin-5 subunit. The two patients were homozygous carriers (parents heterozygous) of a new missense mutation of LAMA3 gene (exon 32: 4300 insA) encoding the alpha3 subunit of laminin-5. Resulting messenger RNA, rapidly degraded, induced an extremely reduced synthesis of alpha3-polypeptide, truncated in its Cterminal domain. DISCUSSION: LAMB3 gene recurrent mutations R636X and R42X account for about 50p. 100 of EBJ cases affecting Caucasians while mutation Q1083X, affecting the same gene, is recurrent in Arab populations. The newly identified mutation results in extremely reduced synthesis of alpha3 chain and truncation of its C-terminal domain, which is crucial for the intermolecular interactions of laminin-5. Our data are in accordance with recent reports suggesting geographical specificity of EBJ mutations linked to founder effects which are amplified by consanguineous marriages in genetically isolated populations. Otherwise, the observation of other unexplored cases of bullous dermatoses with early demise originating from the same region of the two families herein reported highlights the need for the implementation of a prenatal and postnatal diagnostic strategy regarding these genodermatoses. These studies should target LAMA3 and other genes involved in JEB too.

Consanguinity↗
PubMed2004

Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene.

BACKGROUND AND OBJECTIVES: Hemophilia B is an X-linked recessive, bleeding disorder caused by mutations in the factor IX gene. A wide range of mutations, showing large molecular heterogeneity, has been described in hemophilia B patients. Our study was aimed at characterizing mutations in the factor IX gene in a cohort of North Indian hemophilia B patients. DESIGN AND METHODS: Polymerase chain reaction (PCR) amplification and direct sequencing of all regions of likely functional significance- the coding regions, promoter, the 5' UTR, the splice junctions and parts of the 3' UTR of the factor IX gene was done in 18 families carrying a severe form of hemophilia B. RESULTS: We identified 10 point mutations (including 2 novel ones); one novel deletion and one donor splice site mutation. Recurrence of a nonsense and a missense mutation was observed. The mutation in 3 families could not be characterized. None of the 14 polymorphic positions reported in the Haemophilia B Mutation database in the regions sequenced were polymorphic; herein we report four novel synonymous single base mismatches. One mutation reported to be causative in the database was found to be more likely a non-causal polymorphism. INTERPRETATION AND CONCLUSIONS: Our data confirm the remarkable heterogeneity of the mutational spectrum in hemophilia B among affected families. This is the first mutation report on the disease in the Indo-Aryan population from the Indian subcontinent. Identification of a causative mutation leads to more precise carrier detection than does conventional polymorphism-based linkage analysis. This can effectively be used to establish genotype/ phenotype relationships.

Amino Acid Substitution↗
PubMed1994

Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vaso-pressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255de19, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations--R113W, Y128S, R137H, R181C, and R202C--that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methyl-cytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication.

Amino Acid Sequence↗
PubMed2001

Improved detection of CFTR mutations in Southern California Hispanic CF patients.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a common autosomal recessive disease in Caucasians. The broad mutation spectrum varies among different patient groups. Current molecular diagnoses are designed to detect 80-97% of CF chromosomes in Caucasians and Ashkenazi Jews but have a much lower detection rate in Hispanic CF patients. Grebe et al. [1994] reported a 58% detection rate in Hispanic patients. Since then, there has been no large-scale, complete mutational analysis of Hispanic CF patients. In this study, the mutations in 62 Hispanic patients from southern California were investigated. The entire coding and flanking intronic regions of the CFTR gene were analyzed by temporal temperature gradient gel electrophoresis (TTGE) followed by sequencing to identify the mutations. Eleven novel mutations were discovered in this patient group: 3876delA, 406-1G>A, 935delA, 663delT, 3271delGG, 2105-2117del13insAGAAA, 3199del6, Q179K, 2108delA, 3171delC, and 3500-2A>T. Among the mutations, seven were out-of-frame insertions and deletions that result in truncated proteins, two were splice-site mutations, one was an in-frame 6 bp deletion, and one was a missense mutation that involved the non-conservative change of glutamine-179 to lysine. All patients presented severe classical clinical course with pancreatic insufficiency and poor growth, consistent with the nature of truncation mutation. The results indicate that TTGE screening following the analysis of recurrent mutations will substantially improve the mutation detection rate for Hispanic CF patients from southern California.

Alleles↗
PubMed2001

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis.

Germ-line mutations in the 5' half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ-line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ-line mutations and clinical manifestations of the disease.

Adenomatous Polyposis Coli↗
PubMed1995

Mutations and polymorphisms in the human ornithine transcarbamylase gene: mutation update addendum.

This mutation update addendum summarizes 30 new mutations and polymorphisms found in the ornithine transcarbamylase (OTC) gene since the publication in this journal of the first mutation update. Thus, more than 60 mutations and polymorphisms in the OTC gene are currently known. Most of the mutations have been seen in a single family and the few recurrent mutations occurred in CpG dinucleotides. The presumed deleterious effects of most mutations await confirmation by appropriate expression studies. Once the tertiary structure of the enzyme is fully known, and the functional domains established, the effects of mutations, or lack thereof, could be better predicted.

DNA Mutational Analysis↗
PubMed2006

Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.

Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.

Alleles↗
PubMedDate not supplied

Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage enzyme complex (GCS). GCS is a complex of four proteins encoded on four different chromosomes. In classical neonatal NKH, levels of cerebrospinal fluid (CSF) glycine and CSF/plasma glycine ratio are very high but the CSF results, in particular, may be more difficult to interpret in later-onset, milder, or otherwise atypical NKH. Enzymatic confirmation of NKH requires a liver sample. Delineation of which protein of the complex is defective is necessary to screen for mutations in the appropriate gene. Except for Finnish NKH patients, few recurrent mutations have yet been found, although analysis of the P-protein gene (the site of the defect in the majority of patients) is at an early stage. Prenatal diagnosis by GCS assay in chorionic villus biopsies is not completely reliable and will be replaced by molecular analysis in families where the mutations are known.

Animals↗
PubMed1995

The PKU mutation S349P causes complete loss of catalytic activity in the recombinant phenylalanine hydroxylase enzyme.

The mutation S349P in exon 10 of the phenylalanine hydroxylase (PAH) gene was identified in one Norwegian and one Polish phenylketonuria (PKU) allele on a haplotype 1.7 background. This missense mutation in PAH codon 349 is a T to C transition in cDNA position 1267. This mutation has been reported both on haplotype 1 and 4, suggesting recurrent mutation. In two different expression systems, the pET and the pMAL systems of Escherichia coli, it was shown that the S349P mutation, introduced by site directed mutagenesis, results in complete loss of enzymatic activity. Thus, protein instability alone does not seem to be the direct cause of the lack of activity of this PKU mutation as previously reported.

Base Sequence↗
PubMed2026

Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histological and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor.

We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multiregional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a pancreatic tubular/ductal adenocarcinoma; in 5 cases, a poorly differentiated squamous cell carcinoma was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in 2 of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the majority of somatic alterations, supporting a shared clonal origin for the 2 components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in 2 distinct cases (1 case each). Molecular alterations restricted to the invasive component involved mediators of the transforming growth factor-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and squamous cell carcinomas, although in 2 cases, the matched pancreatic tubular/ductal adenocarcinoma shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multiregional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.

Humans↗
PubMed2003

Compound heterozygosity for mutations in the hairless gene causes atrichia with papular lesions.

BACKGROUND: Congenital atrichias represent a complex and heterogeneous group of genodermatoses, which have been shown in several consanguineous families to result from homozygous mutations in the hairless gene (HR). OBJECTIVES: To identify the molecular basis of congenital atrichia in a non-consanguineous family. METHODS: Genetic analysis was carried out in a two-generation family with two children with congenital atrichia and one healthy child. RESULTS: We established a diagnosis of atrichia with papular lesions based on clinical and histopathological data. We identified a heterozygous 11-bp deletion (189-199del) in the two affected children and their mother. In addition, the two affected children and their father were shown to carry a non sense mutation (Q478X), which has previously been described in a Pakistani family. Haplotype analysis revealed that mutation Q478X occurred independently in the two families. CONCLUSIONS: We have identified the first case of compound heterozygosity for mutations in HR as well as the first instance of a recurrent mutation in this gene. These data further expand our understanding of the molecular pathomechanisms underlying congenital atrichias.

Alopecia↗
PubMed2006

Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients.

BACKGROUND: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions. METHODS: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments. RESULTS: We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1-170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected. CONCLUSION: A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.

Adolescent↗
PubMed1995

Identification of mutations in 90 of 121 consecutive symptomatic French patients with a type I protein C deficiency. The French INSERM Network on Molecular Abnormalities Responsible for Protein C and Protein S deficiencies.

By studying the protein C gene of 121 consecutive patients with symptomatic type I protein C deficiency, we detected 55 different candidate mutations in 90 cases. The mutations, 76% of which were missense changes, were distributed throughout the gene. More than half the missense mutations involved Cys, Phe, Pro, or Gly, amino acids known to affect the structure of the polypeptide chain by various mechanisms. Thus, 40% of protein C deficiencies may be caused by polypeptide chain instability rather than a lack of expression of the mutated allele; this may also account for phenotypic heterogeneity. Seventeen of the 55 different mutations were found in apparently unrelated families. Half the French families we studied bore one of these 17 mutations. The wide variety of mutations suggests that both sporadic cases and a founder effect contribute to the spectrum of protein C mutations in a given population. The differences in both unique and recurrent mutations in French and Dutch populations-the only large population samples so far studied-support this hypothesis.

Base Sequence↗
PubMed2001

Two Novel Frame Shift, Recurrent and De Novo Mutations in the ITGB2 (CD18) Gene Causing Leukocyte Adhesion Deficiency in a Highly Inbred North African Population.

We have identified four different mutations causing leukocyte adhesion Deficiency (LAD) in the ITGB2 gene of patients from a highly inbred population. Two were novel single-bp deletions (1497delG and 1920delG) causing frame shift and the two others were the missense mutations G284S and R593C. In our study, the G284S was a recurrent mutation while the R593C occurred de novo. We have also characterized a novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus. Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect. The observation of a heterogeneous spectrum including de novo and recurrent mutations causing LAD in a highly inbred population is rather unexpected. In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

Journal Article↗