A novel mutation in the 12(R)-lipoxygenase (ALOX12B) gene underlies nonbullous congenital ichthyosiform erythroderma.
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Arabs↗
Biomedical subjects
A M Christiano
Publications and source records attributed to A M Christiano.
Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.
Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.
Adult↗
Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.
Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.
Aged↗
Identification of a recurrent mutation in the human hairless gene underlying atrichia with papular lesions.
Identification of mutations in the hairless (HR) gene in patients with atrichia with papular lesions (APL) has proven of critical importance, as it provides a basis for the differentiation between APL and alopecia universalis. The establishment of the diagnostic criteria for APL has triggered the identification of a large number of APL patients among those suspected to suffer from alopecia universalis. This advancement has resulted in the discovery of an increasing number of hairless mutations in both consanguineous and nonconsanguineous APL families. Here, we report the identification of a homozygous mutation, 3434delC, in an APL patient of Arab-Palestinian descent. The proband is a 23-year-old female with generalized scalp and body alopecia. To confirm the diagnosis of APL and to identify the specific mutation, we sequenced the hairless gene. Sequencing of all exons of the hairless gene revealed a homozygous frameshift mutation, 3434delC, in exon 18. Interestingly, the same mutation was previously identified in an Arab-Israeli family. Our data suggest that the 3434delC mutation most likely represents a founder mutation in this geographical region.
Adult↗
Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa.
In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.
Base Sequence↗
Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population.
Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7-generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X.
Alopecia↗
Fishing for new genes in skin biology: impact of cytogenetics on gene discovery.
Research into the field of skin biology has grown exponentially over the past two decades. Even though the fundamental molecular pathways are still not fully understood, there have been significant advances in our understanding of the underlying mechanisms involved in the pathogenesis of genodermatosis. The cloning of many candidate genes involved in the etiology of skin diseases has been facilitated by initial cytogenetic evidence. This review will synthesize recent findings that led to the discovery of candidate genes for anhidrotic ectodermal dysplasia, Williams-Beuren syndrome, neurofibromatosis-I and tricho-rhino-phalangeal syndrome.
Cytogenetics↗
A novel missense mutation in the COL7A1 gene underlies epidermolysis bullosa pruriginosa.
Epidermolysis bullosa (EB) pruriginosa is a subtype of dominant dystrophic EB (DDEB), characterized by severe pruritus and blistering localized to the extensor surface of the extremities. EB pruriginosa exhibits extensive clinical heterogeneity with variable expression and delayed age of onset. Mutations in the COL7A1 gene, especially in glycine residues within Gly-X-Y repeats, have been shown to cause this form of DDEB. Here, we report a novel COL7A1 mutation in a Taiwanese pedigree with EB pruriginosa. Using PCR and direct sequence analysis we have identified a G-->T transversion at nucleotide 7097 in exon 92 of COL7A1, converting a glycine residue to valine (G2366V). The mutation resides within a consecutive, uninterrupted stretch of 17 Gly-X-Y residues in the triple-helical domain of type VII collagen. Interestingly, an affected member of this family also displayed elevated IgE levels, previously reported in some patients with this disorder. Our finding further implicates COL7A1 mutation in the pathogenesis of EB pruriginosa and underscores the heterogeneous clinical symptoms of glycine mutations in DDEB.
Base Sequence↗
Cloning of the breakpoints of a de novo inversion of chromosome 8, inv (8)(p11.2q23.1) in a patient with Ambras syndrome.
Ambras syndrome (AMS) is a unique form of universal congenital hypertrichosis. In patients with this syndrome, the whole body is covered with fine long hair, except for areas where normally no hair grows. There is accompanying facial dysmorphism and teeth abnormalities, including retarded first and second dentition and absence of teeth. In 1993, Baumeister et al. reported an isolated case of Ambras syndrome in association with a pericentric inversion of chromosome 8. Subsequently, another patient with congenital hypertrichosis and rearrangement of chromosome 8 was reported by Balducci et al. (1998). Both of these patients have a breakpoint in 8q22 in common suggesting that this region of chromosome 8 contains a gene involved in regulation of hair growth. In order to precisely determine the nature of the rearrangement in the case of Ambras syndrome, we have used fluorescent in situ hybridization (FISH) analysis. We have cloned the inversion breakpoints in this patient and generated a detailed physical map of the inversion breakpoint interval. Analysis of the transcripts that map in the vicinity of the breakpoints revealed that the inversion does not disrupt a gene, and suggests that the phenotype is caused by a position effect.
Abnormalities, Multiple↗
Congenital universal hypertrichosis with deafness and dental anomalies inherited as an X-linked trait.
We report a large Mexican kindred with a variant form of congenital universal hypertrichosis that is inherited in an apparent X-linked recessive manner. In addition to the generalized hypertrichosis, the affected individuals have dental malformations and deafness. Males are more severely affected than females who exhibit only mild hypertrichosis, but not deafness or dental anomalies. Haplotype analysis in this pedigree revealed linkage to a 13-cM region on chromosome Xq24-q27.1 between markers GATA198A10 and DXS8106. Localization of the gene underlying this form of hypertrichosis is the initial step in identifying genes on the X chromosome that are involved in the control of hair growth and development.
Chromosome Mapping↗
A novel mouse desmosomal cadherin family member, desmoglein 1 gamma.
The mouse desmogleins are members of the desmosomal cadherin superfamily, and are critical structural components of the desmosome. The genes encoding mouse desmogleins are tightly clustered within 600 kb of chromosome 18, within a desmosomal cadherin gene family also containing the three desmocollin genes. In this study, we have characterized a novel mouse desmoglein gene, highly homologous to both mouse and human Dsg1, designated desmoglein 1 gamma (Dsg1c). Dsg1 gamma shares 83% amino acid identity to the previously described mouse Dsg1, now designated as Dsg1 alpha, and 32% and 40% identity to mouse Dsg2 and 3, respectively. The Dsg1 gamma gene maps within the desmosomal gene cluster, between Dsc1 and Dsg1 alpha. Comparison of its exon-intron structure revealed a high level of evolutionary conservation with related family members. In contrast to Dsg1 alpha and Dsg3 whose expression is largely restricted to the skin, Dsg1 gamma is also expressed in the brain, skeletal muscle, and liver, among other tissues, and is thus more similar to Dsg2 in its tissue distribution. Interestingly, an orthologous Dsg1 gamma was not found in the human genome, suggesting that the desmosomal cadherin gene cluster contracted during mammalian evolution.
Amino Acid Motifs↗
Identification of mutations in the COL7A1 gene in a proband with mild recessive dystrophic epidermolysis bullosa and aortic insufficiency.
We report the clinical and molecular findings in a patient with a mild form of recessive dystrophic epidermolysis bullosa and aortic insufficiency. To our knowledge, this is the first report of association between dystrophic epidermolysis bullosa and abnormalities of the aortic valve. Analysis of the COL7A1 gene has revealed two new mutations, a 20-bp duplication and a splice site mutation.
Adult↗
Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix.
Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair resulting from periodic thinning of the shaft (MIM 158000). The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. Mutations of the helix-encoded region in two hair-specific keratins (hHb1 and hHb6) have been identified as responsible for this disorder. We investigated two unrelated families from Russia and Colombia with monilethrix and found two missense mutations in hHb6. In the Russian family, we found a G to A transition at the first base of codon 402, resulting in a lysine substitution (GAG to AAG), designated E402K. In the Colombian family, affected patients carried a missense mutation of codon 413, involving a transition from G to A causing a lysine substitution (GAG to AAG), designated E413K. These two mutations have been identified in other monilethrix families from Europe. Our findings extend the body of evidence implicating recurrent hHb6 and hHb1 mutations in monilethrix families from around the world.
Colombia↗
Identification of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2.
Pachyonychia congenita is characterized by hypertrophic nail dystrophy and associated ectodermal features. PC-1 subtype is associated with mutations in keratins 6a or 16, whereas PC-2 subtype is linked to mutations in keratins 6b or 17. The correlation between the mutated gene and the type of PC has generally been consistent. In this report, we describe a case with overlapping clinical features of PC-1 and PC-2 in which a mutation in K6a was identified.
Adult↗
Atrichia with papular lesions resulting from a novel homozygous missense mutation in the hairless gene.
Atrichia with papular lesions (APL) is a rare autosomal recessive disorder resulting in complete and irreversible hair loss shortly after birth. Affected individuals also develop papular lesions of keratin-filled follicular cysts over extensive areas of the body. Mutations in the hairless gene, a putative single zinc-finger transcription factor protein, have been implicated in the pathogenesis of APL. In this report, we describe a novel missense mutation, E583V, in the hairless gene in an Italian family affected with APL. The mutation resides between the LXXLL motif found in TRIPs (thyroid hormone receptor interacting proteins) in exon 5 and the six-cysteine zinc-finger motif in exon 6. The amino acid sequence neighbouring the LXXLL motif and zinc-finger domain is highly conserved in human, monkey, rat, and mouse hairless proteins. Our finding extends the body of evidence that supports the importance of the zinc-finger and LXXLL domains in the function of the hairless protein. Moreover, we continue to find small APL families without consanguinity from around the world.
Alopecia↗
Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.
BACKGROUND: The identification of the molecular basis of disorders of keratinisation has significantly advanced our understanding of skin biology, revealing new information on key structures in the skin, such as the intermediate filaments, desmosomes, and gap junctions. Among these disorders, there is an extraordinarily heterogeneous group known as palmoplantar keratodermas (PPK), for which only a few molecular defects have been described. A particular form of PPK, known as punctate PPK, has been described in a few large autosomal dominant pedigrees, but its genetic basis has yet to be identified. AIM: Identification of the gene for punctate PPK. METHODS: Clinical examination and linkage analysis in three families with punctate PPK. RESULTS: A genomewide scan was performed on an extended autosomal dominant pedigree, and linkage to chromosome 15q22-q24 was identified. With the addition of two new families with the same phenotype, we confirmed the mapping of the locus for punctate PPK to a 9.98 cM interval, flanked by markers D15S534 and D15S818 (maximum two point lod score of 4.93 at theta = 0 for marker D15S988). CONCLUSIONS: We report the clinical and genetic findings in three pedigrees with the punctate form of PPK. We have mapped a genetic locus for this phenotype to chromosome 15q22-q24, which indicates the identification of a new gene involved in skin integrity.
Chromosome Mapping↗
A recurrent mutation in the loricrin gene underlies the ichthyotic variant of Vohwinkel syndrome.
Vohwinkel syndrome (VS) is a family of genodermatoses which exhibits extensive clinical and genetic heterogeneity. Here, we studied a pedigree originating from the UK with typical features of the ichthyotic variant of VS and identified a recurrent insertion mutation in the loricrin gene resulting in a mutant polypeptide with an unusual C terminus. Functional studies in transgenic mice have shown that the accumulation of mutant loricrin in the nucleus appears to interfere with the later stages of epidermal differentiation, thereby explaining the clinical manifestations of ichthyosis, keratoderma and pseudoainhum. Our findings extend the body of evidence implicating mutations in the loricrin gene as the underlying cause of VS.
Female↗
Complex cytogenetic rearrangement of chromosome 8q in a case of Ambras syndrome.
Ambras syndrome (AMS) is a unique form of congenital universal hypertrichosis. The syndrome has been found in association with rearrangements of chromosome 8 in two isolated cases. One of these patients was reported to have an apparently balanced paracentric inversion of chromosome 8, inv(8)(q12q22). Our cytogenetic analysis on this patient showed that the rearrangement of chromosome 8 is more complex than initially reported. We detected an insertion of the q23-q24 region into a more proximal region of the long arm of chromosome 8 as well as a large deletion in 8q23:46,XX, rea(8)(8pter-->8q13::8q23.2-->8q24.1::8q13-->8q23.1::8q24.1-->8qter). Given the large number of breakpoints and the presence of a substantial deletion, it is surprising that the proposita did not show anomalies other than these characteristic of Ambras syndrome.
Child, Preschool↗