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Dive into the research topics where Leena Pulkkinen is active.

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Featured researches published by Leena Pulkkinen.


Nature Genetics | 1996

Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.

F.J.D. Smith; Robin A.J. Eady; Irene M. Leigh; James R. McMillan; E.L. Rugg; David P. Kelsell; Stephen P. Bryant; Nigel K. Spurr; J.F. Geddes; G. Kirtschig; G. Milana; A.G. de Bono; Katsushi Owaribe; Gerhard Wiche; Leena Pulkkinen; Jouni Uitto; W.H.I. McLean; E. B. Lane

We report that mutation in the gene for plectin, a cytoskeleton–membrane anchorage protein, is a cause of autosomal recessive muscular dystrophy associated with skin blistering (epidermolysis bullosa simplex). The evidence comes from absence of plectin by antibody staining in affected individuals from four families, supportive genetic analysis (localization of the human plectin gene to chromosome 8q24.13–qter and evidence for disease segregation with markers in this region) and finally the identification of a homozygous frameshift mutation detected in plectin cDNA. Absence of the large multifunctional cytoskeleton protein plectin can simultaneously account for structural failure in both muscle and skin.


Matrix Biology | 1999

Mutation analysis and molecular genetics of epidermolysis bullosa

Leena Pulkkinen; Jouni Uitto

Cutaneous basement membrane zone (BMZ) consists of a number of attachment structures that are critical for stable association of the epidermis to the underlying dermis. These include hemidesmosomes, anchoring filaments and anchoring fibrils which form an interconnecting network extending from the intracellular milieu of basal keratinocytes across the dermal-epidermal basement membrane to the underlying dermis. Aberrations in this network structure, e.g. due to genetic lesions in the corresponding genes, can result in fragility of the skin at the level of the cutaneous BMZ. The prototype of such diseases is epidermolysis bullosa (EB), a heterogeneous group of genodermatoses characterized by fragility and blistering of the skin, often associated with extracutaneous manifestations, and inherited either in an autosomal dominant or autosomal recessive manner. Based on constellations of the phenotypic manifestations, severity of the disease, and the level of tissue separation within the cutaneous BMZ, EB has been divided into clinically distinct subcategories, including the simplex, hemidesmosomal, junctional and dystrophic variants. Elucidation of BMZ gene/protein systems and development of mutation detection strategies have allowed identification of mutations in 10 different BMZ genes which can explain the clinical heterogeneity of EB. These include mutations in the type VII collagen gene (COL7A1) in the dystrophic (severely scarring) forms of EB; mutations in the laminin 5 genes (LAMA3, LAMB3 and LAMC2) in a lethal (Herlitz) variant of junctional EB; aberrations in the type XVII collagen gene (COL17A1) in non-lethal forms of junctional EB; mutations in the alpha6 and beta4 integrin genes in a distinct hemidesmosomal variant of EB with congenital pyloric atresia; and mutations in the plectin gene (PLEC1) in a form of EB associated with late-onset muscular dystrophy. Identification of mutations in these gene/protein systems attests to their critical importance in the overall stability of the cutaneous BMZ. Furthermore, elucidation of mutations in different variants of EB has direct clinical applications in terms of refined classification, improved genetic counseling, and development of DNA-based prenatal testing in families with EB.


Cell | 1997

Revertant Mosaicism in Epidermolysis Bullosa Caused by Mitotic Gene Conversion

Marcel F. Jonkman; H Scheffer; Rein P. Stulp; Hendri H. Pas; Miranda Nijenhuis; Klaas Heeres; Katsushi Owaribe; Leena Pulkkinen; Jouni Uitto

Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles. Specifically, the maternal allele surrounding the mutation site on COL17A1 (1706delA) showed reversion of the mutation and loss of heterozygosity along a tract of at least 381 bp in revertant keratinocytes derived from clinically unaffected skin patches; the paternal mutation (R1226X) remained present in all cell samples. Revertant mosaicism represents a way of natural gene therapy.


Molecular and Cellular Biology | 2005

Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

John F. Klement; Yasushi Matsuzaki; Qiujie Jiang; Joseph Terlizzi; Hae Young Choi; Norihiro Fujimoto; Kehua Li; Leena Pulkkinen; David E. Birk; John P. Sundberg; Jouni Uitto

ABSTRACT Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6−/− mice but was not observed in Abcc6 +/− or Abcc6 +/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6 −/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease.


Trends in Molecular Medicine | 2001

Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment–genome interface?

Jouni Uitto; Leena Pulkkinen; Franziska Ringpfeil

Pseudoxanthoma elasticum (PXE) is a relatively rare heritable disorder affecting the skin, eyes and cardiovascular system, with considerable morbidity and mortality. The disease affects the elastic fibers of affected organs, which become progressively calcified. Thus, PXE has been considered as a prototypic heritable connective tissue disorder affecting the elastic fiber system. Recently, PXE has been linked to mutations in the MRP6/ABCC6 gene, a member of the ABC transporter family, expressed primarily in the liver and the kidneys. This information, together with clinical observations suggesting environmental, hormonal and/or dietary modulation of the disease, raises the intriguing possibility that PXE is a primary metabolic disorder at the environment-genome interface.


Experimental Dermatology | 1996

Plectin and human genetic disorders of the skin and muscle. The paradigm of epidermolysis bullosa with muscular dystrophy.

Jouni Uitto; Leena Pulkkinen; Frances Jd Smith; W.H. Irwin McLean

Abstract Recent progress in understanding the molecular organization of the cutaneous basement membrane zone (BMZ) has revealed an intricate network of structural proteins necessary for stable association of the epidermis to the underlying dermis. Molecular genetics of the cutaneous BMZ has also revealed that defects in as many as nine distinct genes within the dermal‐epidermal junction which result in different forms of epidermolysis bullosa (EB). a group of heritable mechano‐bullous disorders. We have recently demonstrated that a variant of EB associated with late‐onset development of muscular dystrophy (EB‐MD. MIM no. 226670) results from mutations in the gene encoding plectin (PLEC1). a cytoskeleton associated attachment protein present in the hemidesmosomal inner plaque and the sarcolemma of the muscle. Consequently, mutations in this multi‐functional gene/protein system can result in phenotypic manifestations of EB‐MD both in the skin and the muscle. In this overview, we will summarize the domain organization of plectin and the structure of the corresponding gene (PLEC1). as well as the genetic basis of EB‐MD in families studied thus far. Elucidation of the molecular basis of this subtype of EB adds to our understanding of the structural and functional complexity of the cutaneous BMZ.


Human Genetics | 2002

Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs non-Herlitz phenotypes

Aoi Nakano; Sheau-Chiou Chao; Leena Pulkkinen; Dédée F. Murrell; Leena Bruckner-Tuderman; Ellen Pfendner; Jouni Uitto

Abstract. Junctional epidermolysis bullosa (JEB) is a group of heritable blistering diseases in which tissue separation occurs within the lamina lucida of the cutaneous basement membrane zone. Clinically, two broad subcategories have been recognized: The Herlitz variant (H-JEB; OMIM 226700) is characterized by early demise of the affected individuals, usually within the first year of life, while non-Herlitz (nH-JEB; OMIM 226650) patients show a milder phenotype with life-long blistering, yet with normal lifespan. In this study, we have examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz JEB, for mutations in the candidate genes, LAMA3, LAMB3, and LAMC2, encoding the subunit polypeptides of laminin 5. The mutation detection strategy consisted of PCR amplification of all exons in these genes, followed by heteroduplex scanning and nucleotide sequencing. We were able to identify pathogenic mutations in both alleles of each proband, the majority of the mutations being in the LAMB3 gene. Examination of the mutation database revealed that most cases with Herlitz JEB harbored premature termination codon (PTC) mutations in both alleles. In non-Herlitz cases, the PTC mutation was frequently associated with a missense mutation or a putative splicing mutation in trans. In three cases with putative splicing mutations, RT-PCR analysis revealed a repertoire of splice variants in-frame, predicting the synthesis of either shortened or lengthened, yet partly functional, polypeptides. These observations would explain the relatively mild phenotype in cases with splicing mutations. Collectively, these findings, together with the global laminin 5 mutation database, contribute to our understanding of the genotype/phenotype correlations explaining the Herlitz vs non-Herlitz phenotypes.


International Journal of Dermatology | 2000

The gene gun: current applications in cutaneous gene therapy

Michael T.S. Lin; Leena Pulkkinen; Jouni Uitto; Kyonggeun Yoon

Keratinization disorders Epidermolytic hyperkeratosis KRT1, KRT10 12 Epidermolytic PPK KRT9 12 Non-epidermolytic PPK KRT16 12 Vohwinkel’s syndrome LOR 31 Ichthyosis bullosa Siemens KRT2e 64 Pachonychia congenita type 1/2 KRT6a, 16, 17 64 X-linked ichthyosis STS 7 Lamellar ichthyosis TGM1 31 Palmoplantar keratoderma GJB2 61 with deafness Erythrokeratodermia variabilis GJB3 60 Darier’s disease ATP2A2 66 Striate palmoplantar keratoderma DSP 2 Striate keratoderma DSG1 62


Experimental Dermatology | 1998

Hemidesmosomal variants of epidermolysis bullosa

Leena Pulkkinen; Jouni Uitto

Abstract: Epidermolysis bullosa (EB), a heterogeneous group of genodermatoses, is characterized by fragility and blistering of the skin, associated with characteristic extracutaneous manifestations. Based on clinical severity, constellation of the phenotypic manifestations, and the level of tissue separation within the cutaneous basement membrane zone, EB has been divided into distinct subcategories. Traditionally, these include the simplex, junctional and dystrophic variants of EB. Recent attention has been drawn to variants of EB demonstrating tissue separation at the level of hemidesmosomes, ultrastructurally recognizable adhesion complexes within the cutaneous basement membrane zone. Clinically, these hemidesmosomal variants manifest either as generalized atrophic benign epidermolysis bullosa (GABEB), EB with pyloric atresia, or EB with late‐onset muscular dystrophy, Elucidation of basement membrane zone components by molecular cloning and development of mutation detection strategies have revealed that the hemidesmosomal variants of EB result from mutations in the genes encoding the subunit polypeptides of the 180‐kD bullous pemphigoid antigen/type XVII collagen, the α6β4 integrin, or plectin, respectively. Collectively, these data add to the understanding of the molecular complexity of the cutaneous basement membrane zone in EB, as attested by the fact that mutations in 10 different genes can underlie different variants of EB. Elucidation of mutations in different forms of EB has direct application to genetic counseling and DNA‐based prenatal testing in families with EB.


American Journal of Human Genetics | 1998

Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense

Leena Pulkkinen; Fatima Rouan; Leena Bruckner-Tuderman; Robert Wallerstein; Maria C. Garzon; Tod Brown; Lynne T. Smith; William B. Carter; Jouni Uitto

Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital pyloric atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the alpha6 beta4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination-codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for alpha6 and beta4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.

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Jean-Paul Ortonne

University of Nice Sophia Antipolis

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Aoi Nakano

Thomas Jefferson University

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Fatima Rouan

Thomas Jefferson University

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