The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis

被引:115
作者
Sprecher, E
Chavanas, S
DiGiovanna, JJ
Amin, S
Nielsen, K
Prendiville, JS
Silverman, R
Esterly, NB
Spraker, MK
Guelig, E
de Luna, ML
Williams, ML
Buehler, B
Siegfried, EC
Van Maldergem, L
Pfendner, E
Bale, SJ
Uitto, J
Hovnanian, A
Richard, G
机构
[1] Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA
[3] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England
[4] Brown Univ, Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA
[5] NCI, NIH, Providence, RI USA
[6] British Columbia Childrens Hosp, Dept Pediat, Vancouver, BC V6H 3V4, Canada
[7] Georgetown Univ, Dept Dermatol, Washington, DC USA
[8] Choldrens Hosp Milwaukee, Dept Pediat, Milwaukee, WI USA
[9] Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA
[10] Wellsboro Family Praxis, Wellsboro, PA USA
[11] Hosp JM Ramos Majia, Dept Pediat, Buenos Aires, DF, Argentina
[12] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA
[13] Univ Nebraska, Med Ctr, Dept Clin Genet, Omaha, NE USA
[14] NIAMS, NIH, Bethesda, MD USA
[15] GeneDx Rockville, Rockville, MD USA
[16] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA
[17] Ctr Genet Med, Inst Pathol & Genet, Gerpinnes, Belgium
关键词
atopic dermatitis; congenital recessive ichthyosis; hair abnormalities; linkage analysis; serine proteinase inhibitors;
D O I
10.1046/j.1523-1747.2001.01389.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
The Comel-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comel-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comel-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comel-Netherton syndrome across families of different origins. The Comel-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comel-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic. sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comel-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comel-Netherton syndrome.
引用
收藏
页码:179 / 187
页数:9
相关论文
共 43 条
[1]   Cloning and characterization of hurpin (protease inhibitor 13):: A new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family [J].
Abts, HF ;
Welss, T ;
Mirmohammadsadegh, A ;
Köhrer, K ;
Michel, G ;
Ruzicka, T .
JOURNAL OF MOLECULAR BIOLOGY, 1999, 293 (01) :29-39
[2]  
ALKEMADE JAC, 1994, J CELL SCI, V107, P2335
[3]   NATURAL PROTEIN PROTEINASE-INHIBITORS AND THEIR INTERACTION WITH PROTEINASES [J].
BODE, W ;
HUBER, R .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1992, 204 (02) :433-451
[4]   NETHERTONS SYNDROME IN 2 ADULT BROTHERS [J].
CAPUTO, R ;
VANOTTI, P ;
BERTANI, E .
ARCHIVES OF DERMATOLOGY, 1984, 120 (02) :220-222
[5]   Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping [J].
Chavanas, S ;
Garner, C ;
Bodemer, C ;
Ali, M ;
Hamel-Teillac, D ;
Wilkinson, J ;
Bonafé, JL ;
Paradisi, M ;
Kelsell, DP ;
Ansai, S ;
Mitsuhashi, Y ;
Larrègue, M ;
Leigh, IM ;
Harper, JI ;
Taïeb, A ;
de Prost, Y ;
Cardon, LR ;
Hovnanian, A .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (03) :914-921
[6]   Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome [J].
Chavanas, S ;
Bodemer, C ;
Rochat, A ;
Hamel-Teillac, D ;
Ali, M ;
Irvine, AD ;
Bonafé, JL ;
Wilkinson, J ;
Taïeb, A ;
Barrandon, Y ;
Harper, JI ;
de Prost, Y ;
Hovnanian, A .
NATURE GENETICS, 2000, 25 (02) :141-142
[7]  
COMEL M, 1949, Dermatologica, V98, P133
[8]  
DeWolf K, 1995, AM J DERMATOPATH, V17, P606
[9]  
DUPRE A, 1978, ANN DERMATOL VENER, V105, P49
[10]   Expression of stratum corneum chymotryptic enzyme in relation to other markers of epidermal differentiation in a skin explant model [J].
Ekholm, E ;
Egelrud, T .
EXPERIMENTAL DERMATOLOGY, 2000, 9 (01) :65-70