4q58

Structural highlights

Disease

[PLEC_HUMAN] Defects in PLEC are the cause of epidermolysis bullosa simplex with pyloric atresia (EBS-PA) [MIM:612138]. EBS-PA is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. This disorder is allelic to MD-EBS.^{[1] [2] [3]} Defects in PLEC are the cause of epidermolysis bullosa simplex with muscular dystrophy (MD-EBS) [MIM:226670]. MD-EBS is an autosomal recessive disorder characterized by epidermal blister formation at the level of the hemidesmosome and associated with late-onset muscular dystrophy. Defects in PLEC are the cause of epidermolysis bullosa simplex Ogna type (O-EBS) [MIM:131950]; also called epidermolysis bullosa simplex 1. O-EBS is a form of intraepidermal epidermolysis bullosa characterized by generalized skin bruising, skin fragility with non-scarring blistering and small hemorrhagic blisters on hands. At the ultrastructural level, it is differentiated from classical cases of K-EBS, WC-EBS and DM-EBS, by the occurrence of blisters originating in basal cells above hemidesmosomes, and abnormal hemidesmosome intracellular attachment plates. Defects in PLEC are the cause of limb-girdle muscular dystrophy type 2Q (LGMD2Q) [MIM:613723]. An autosomal recessive degenerative myopathy characterized by early childhood onset of proximal muscle weakness. Note=A 9 bp deletion containing the initiation codon in exon 1f of PLEC have been found in limb-girdle muscular dystrophy patients. The mutation results in deficient expression of isoform 9 and disorganization of the myofibers, without any effect on the skin.^{[4] [5]} [ITB4_HUMAN] Defects in ITGB4 are a cause of epidermolysis bullosa letalis with pyloric atresia (EB-PA) [MIM:226730]; also known as junctional epidermolysis bullosa with pyloric atresia (PA-JEB) or aplasia cutis congenita with gastrointestinal atresia. EB-PA is an autosomal recessive, frequently lethal, epidermolysis bullosa with variable involvement of skin, nails, mucosa, and with variable effects on the digestive system. It is characterized by mucocutaneous fragility, aplasia cutis congenita, and gastrointestinal atresia, which most commonly affects the pylorus. Pyloric atresia is a primary manifestation rather than a scarring process secondary to epidermolysis bullosa.^{[6] [7] [8] [9] [10] [11] [12]} Defects in ITGB4 are a cause of generalized atrophic benign epidermolysis bullosa (GABEB) [MIM:226650]. GABEB is a non-lethal, adult form of junctional epidermolysis bullosa characterized by life-long blistering of the skin, associated with hair and tooth abnormalities.^[13]

Function

[PLEC_HUMAN] Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofibers integrity.^{[14] [15]} [ITB4_HUMAN] Integrin alpha-6/beta-4 is a receptor for laminin. Plays a critical structural role in the hemidesmosome of epithelial cells. Is required for the regulation of keratinocyte polarity and motility.^{[16] [17]}

References

1. ↑ McLean WH, Pulkkinen L, Smith FJ, Rugg EL, Lane EB, Bullrich F, Burgeson RE, Amano S, Hudson DL, Owaribe K, McGrath JA, McMillan JR, Eady RA, Leigh IM, Christiano AM, Uitto J. Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization. Genes Dev. 1996 Jul 15;10(14):1724-35. PMID:8698233
2. ↑ Natsuga K, Nishie W, Shinkuma S, Arita K, Nakamura H, Ohyama M, Osaka H, Kambara T, Hirako Y, Shimizu H. Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. Hum Mutat. 2010 Oct;31(10):E1687-98. doi: 10.1002/humu.21330. PMID:20665883 doi:10.1002/humu.21330
3. ↑ Charlesworth A, Gagnoux-Palacios L, Bonduelle M, Ortonne JP, De Raeve L, Meneguzzi G. Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. J Invest Dermatol. 2003 Dec;121(6):1344-8. PMID:14675180 doi:12639
4. ↑ Gundesli H, Talim B, Korkusuz P, Balci-Hayta B, Cirak S, Akarsu NA, Topaloglu H, Dincer P. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet. 2010 Dec 10;87(6):834-41. doi: 10.1016/j.ajhg.2010.10.017. Epub, 2010 Nov 25. PMID:21109228 doi:10.1016/j.ajhg.2010.10.017
5. ↑ McLean WH, Pulkkinen L, Smith FJ, Rugg EL, Lane EB, Bullrich F, Burgeson RE, Amano S, Hudson DL, Owaribe K, McGrath JA, McMillan JR, Eady RA, Leigh IM, Christiano AM, Uitto J. Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization. Genes Dev. 1996 Jul 15;10(14):1724-35. PMID:8698233
6. ↑ Pulkkinen L, Rouan F, Bruckner-Tuderman L, Wallerstein R, Garzon M, Brown T, Smith L, Carter W, Uitto J. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet. 1998 Nov;63(5):1376-87. PMID:9792864 doi:S0002-9297(07)61568-7
7. ↑ Pulkkinen L, Kim DU, Uitto J. Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4). Am J Pathol. 1998 Jan;152(1):157-66. PMID:9422533
8. ↑ Pulkkinen L, Bruckner-Tuderman L, August C, Uitto J. Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of epidermolysis bullosa with pyloric atresia. Am J Pathol. 1998 Apr;152(4):935-41. PMID:9546354
9. ↑ Mellerio JE, Pulkkinen L, McMillan JR, Lake BD, Horn HM, Tidman MJ, Harper JI, McGrath JA, Uitto J, Eady RA. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol. 1998 Nov;139(5):862-71. PMID:9892956
10. ↑ Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D'Agati VD. Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis. 2000 Jul;36(1):190-6. PMID:10873890
11. ↑ Ashton GH, Sorelli P, Mellerio JE, Keane FM, Eady RA, McGrath JA. Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia. Br J Dermatol. 2001 Feb;144(2):408-14. PMID:11251584
12. ↑ Nakano A, Pulkkinen L, Murrell D, Rico J, Lucky AW, Garzon M, Stevens CA, Robertson S, Pfendner E, Uitto J. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res. 2001 May;49(5):618-26. PMID:11328943
13. ↑ Inoue M, Tamai K, Shimizu H, Owaribe K, Nakama T, Hashimoto T, McGrath JA. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol. 2000 May;114(5):1061-4. PMID:10792571 doi:10.1046/j.1523-1747.2000.00960-3.x
14. ↑ Koster J, Geerts D, Favre B, Borradori L, Sonnenberg A. Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly. J Cell Sci. 2003 Jan 15;116(Pt 2):387-99. PMID:12482924
15. ↑ Gundesli H, Talim B, Korkusuz P, Balci-Hayta B, Cirak S, Akarsu NA, Topaloglu H, Dincer P. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet. 2010 Dec 10;87(6):834-41. doi: 10.1016/j.ajhg.2010.10.017. Epub, 2010 Nov 25. PMID:21109228 doi:10.1016/j.ajhg.2010.10.017
16. ↑ Koster J, Geerts D, Favre B, Borradori L, Sonnenberg A. Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly. J Cell Sci. 2003 Jan 15;116(Pt 2):387-99. PMID:12482924
17. ↑ Hamill KJ, Hopkinson SB, DeBiase P, Jones JC. BPAG1e maintains keratinocyte polarity through beta4 integrin-mediated modulation of Rac1 and cofilin activities. Mol Biol Cell. 2009 Jun;20(12):2954-62. doi: 10.1091/mbc.E09-01-0051. Epub 2009, Apr 29. PMID:19403692 doi:10.1091/mbc.E09-01-0051