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Open Access 01-12-2013 | Research

Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family

Authors: Obaid Ur Rahman, Nadeem Khawar, Muhammad Aman Khan, Jawad Ahmed, Kamran Khattak, Jumana Yousuf Al-Aama, Muhammad Naeem, Musharraf Jelani

Published in: Diagnostic Pathology | Issue 1/2013

Abstract

Background

Congenital generalized lipodystrophy (CGL) also known as Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a genetically heterogeneous disorder characterized by loss of adipose tissues, Acanthosis nigricans, diabetes mellitus, muscular hypertrophy, hepatomegaly and hypertriglyceridemia. There are four subclinical phenotypes of CGL (CGL1-4) and mutations in four genes AGPAT2, BSCL2, CAV1 and PTRF have been assigned to each type.

Methods

The study included clinical and molecular investigations of CGL disease in a consanguineous Pakistani family. For mutation screening all the coding exons including splice junctions of AGPAT2, BSCL2, CAV1 and PTRF genes were PCR amplified and sequenced directly using an automated DNA sequencer ABI3730.

Results

Sequence analysis revealed a single base pair deletion mutation (c.636delC; p.Tyr213ThrfsX20) in exon 5 of BSCL2 gene causing a frame shift and premature termination codon.

Conclusion

Mutation identified here in BSCL2 gene causing congenital generalized lipodystrophy is the first report in Pakistani population. The patients exhibited characteristic features of generalized lipodystrophy, Acanthosis nigricans, diabetes mellitus and hypertrophic cardiomyopathy.

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Van Maldergem L, Magre J, Khallouf TE, Gedde-Dahl T, Delepine M, Trygstad O, Seemanova E, Stephenson T, Albott CS, Bonnici F: Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet. 2002, 39 (10): 722-733.PubMedCentralCrossRefPubMed

Simha V, Garg A: Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol Metab. 2003, 88 (11): 5433-5437.CrossRefPubMed

Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002, 31 (1): 21-23.CrossRefPubMed

Fu M, Kazlauskaite R, Baracho Mde F, Santos MG, Brandao-Neto J, Villares S, Celi FS, Wajchenberg BL, Shuldiner AR: Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects. J Clin Endocrinol Metab. 2004, 89 (6): 2916-2922.PubMedCentralCrossRefPubMed

Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001, 28 (4): 365-370.CrossRefPubMed

Rognum TO, Bjerve KS, Seip M, Trygstad O, Oseid S: Fat cell size and lipid content of subcutaneous tissue in congenital generalized lipodystrophy. Acta Endocrinol. 1978, 88 (1): 182-189.PubMed

Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O'Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A: Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003, 88 (10): 4840-4847.CrossRefPubMed

Agarwal AK, Barnes RI, Garg A: Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord. 2004, 28 (2): 336-339.PubMed

Gomes KB, Pardini VC, Ferreira AC, Fernandes AP: Phenotypic heterogeneity in biochemical parameters correlates with mutations in AGPAT2 or Seipin genes among Berardinelli-Seip congenital lipodystrophy patients. J Inherit Metab Dis. 2005, 28 (6): 1123-1131.CrossRefPubMed

10.

Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR: Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008, 93 (4): 1129-1134.CrossRefPubMed

11.

Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, Park YE, Nonaka I, Hino-Fukuyo N, Haginoya K: Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009, 119 (9): 2623-2633.PubMedCentralCrossRefPubMed

12.

Jelani M, Chishti MS, Ahmad W: Mutation in PVRL4 gene encoding nectin-4 underlies ectodermal-dysplasia-syndactyly syndrome (EDSS1). J Hum Genet. 2011, 56 (5): 352-357.CrossRefPubMed

13.

Rozen S, Skaletsky H: Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000, 132: 365-386.PubMed

14.

Jin J, Cao L, Zhao Z, Shen S, Kiess W, Zhi D, Ye R, Cheng R, Chen L, Yang Y: Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus. Eur J Endocrinol/Eur Fed Endocrine Soc. 2007, 157 (6): 783-787.CrossRef

15.

Nishiyama A, Yagi M, Awano H, Okizuka Y, Maeda T, Yoshida S, Takeshima Y, Matsuo M: Two Japanese infants with congenital generalized lipodystrophy due to BSCL2 mutations. Pediatr Int. 2009, 51 (6): 775-779.CrossRefPubMed

16.

van de Warrenburg BP, Scheffer H, van Eijk JJ, Versteeg MH, Kremer H, Zwarts MJ, Schelhaas HJ, van Engelen BG: BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy. Neuromuscul Disord. 2006, 16 (2): 122-125.CrossRefPubMed

17.

Friguls B, Coroleu W, del Alcazar R, Hilbert P, Van Maldergem L, Pintos-Morell G: Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation. Eur J Med Genet. 2009, 52 (1): 14-16.CrossRefPubMed

18.

Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, Malli R, Reed JA, Dierick I, Verpoorten N: Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004, 36 (3): 271-276.CrossRefPubMed

19.

Cafforio G, Calabrese R, Morelli N, Mancuso M, Piazza S, Martinuzzi A, Bassi MT, Crippa F, Siciliano G: The first Italian family with evidence of pyramidal impairment as phenotypic manifestation of Silver syndrome BSCL2 gene mutation. Neurol Sci. 2008, 29 (3): 189-191.CrossRefPubMed

20.

Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G: Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005, 57 (3): 415-424.CrossRefPubMed

21.

Brusse E, Majoor-Krakauer D, de Graaf BM, Visser GH, Swagemakers S, Boon AJ, Oostra BA, Bertoli-Avella AM: A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?. Neurogenetics. 2009, 10 (4): 289-297.PubMedCentralCrossRefPubMed

22.

Choi BO, Park MH, Chung KW, Woo HM, Koo H, Chung HK, Choi KG, Park KD, Lee HJ, Hyun YS: Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2. Neurogenetics. 2013, 14 (1): 35-42.CrossRefPubMed

23.

Luigetti M, Fabrizi GM, Madia F, Ferrarini M, Conte A, Delgrande A, Tonali PA, Sabatelli M: Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs. Muscle Nerve. 2010, 42 (3): 448-451.CrossRefPubMed

24.

Lundin C, Nordstrom R, Wagner K, Windpassinger C, Andersson H, von Heijne G, Nilsson I: Membrane topology of the human seipin protein. FEBS Lett. 2006, 580 (9): 2281-2284.CrossRefPubMed

25.

Boutet E, El Mourabit H, Prot M, Nemani M, Khallouf E, Colard O, Maurice M, Durand-Schneider AM, Chretien Y, Gres S: Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie. 2009, 91 (6): 796-803.CrossRefPubMed

26.

Chen W, Chang B, Saha P, Hartig SM, Li L, Reddy VT, Yang Y, Yechoor V, Mancini MA, Chan L: Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Mol Cell Biol. 2012, 32 (6): 1099-1111.PubMedCentralCrossRefPubMed

27.

Miranda DM, Wajchenberg BL, Calsolari MR, Aguiar MJ, Silva JM, Ribeiro MG, Fonseca C, Amaral D, Boson WL, Resende BA: Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome. Clin Endocrinol. 2009, 71 (4): 512-517.CrossRef

28.

Yagi T, Ito D, Nihei Y, Ishihara T, Suzuki N: N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress. Hum Mol Genet. 2011, 20 (19): 3831-3840.CrossRefPubMed

29.

Cho HJ, Sung DH, Ki CS: Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy. Muscle Nerve. 2007, 36 (3): 384-386.CrossRefPubMed

30.

Ito D, Suzuki N: Seipin/BSCL2-related motor neuron disease: Seipinopathy is a novel conformational disease associated with endoplasmic reticulum stress. Clinical neurology. 2007, 47 (6): 329-335.PubMed

31.

Ebihara K, Kusakabe T, Masuzaki H, Kobayashi N, Tanaka T, Chusho H, Miyanaga F, Miyazawa T, Hayashi T, Hosoda K: Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene. J Clin Endocrinol Metab. 2004, 89 (5): 2360-2364.CrossRefPubMed

32.

Shirwalkar HU, Patel ZM, Magre J, Hilbert P, Van Maldergem L, Mukhopadhyay RR, Maitra A: Congenital generalized lipodystrophy in an Indian patient with a novel mutation in BSCL2 gene. J Inherit Metab Dis. 2008, 31 (Suppl 2): S317-S322.CrossRefPubMed

33.

Mandal K, Aneja S, Seth A, Khan A: Berardinelli-Seip congenital lipodystrophy. Indian Pediatr. 2006, 43 (5): 440-445.PubMed

34.

Jeninga EH, de Vroede M, Hamers N, Breur JM, Verhoeven-Duif NM, Berger R, Kalkhoven E: A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction. JIMD reports. 2012, 4: 47-54.PubMedCentralCrossRefPubMed

35.

Agarwal AK, Garg A: Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genomics Hum Genet. 2006, 7: 175-199.CrossRefPubMed

36.

Rajab A, Bappal B, Al-Shaikh H, Al-Khusaibi S, Mohammed AJ: Common autosomal recessive diseases in Oman derived from a hospital-based registry. Community Genet. 2005, 8 (1): 27-30.CrossRefPubMed

37.

Chkioua L, Khedhiri S, Ben Turkia H, Chahed H, Ferchichi S, Ben Dridi MF, Laradi S, Miled A: Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population. Diagn Pathol. 2011, 6: 113-PubMedCentralCrossRefPubMed

38.

Ferenci P: Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum Genet. 2006, 120 (2): 151-159.CrossRefPubMed

39.

Elmahmoudi H, Khodjet-el-khil H, Wigren E, Jlizi A, Zahra K, Pellechia D, Vinciguerra C, Meddeb B, Elggaaied AB, Gouider E: First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations. Diagn Pathol. 2012, 7: 93-PubMedCentralCrossRefPubMed

40.

Khateeb B, Moatter T, Shaghil AM, Haroon S, Kakepoto GN: Genetic diversity of beta-thalassemia mutations in Pakistani population. J Pak Med Assoc. 2000, 50 (9): 293-296.PubMed

Title: Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family
Authors: Obaid Ur Rahman
Nadeem Khawar
Muhammad Aman Khan
Jawad Ahmed
Kamran Khattak
Jumana Yousuf Al-Aama
Muhammad Naeem
Musharraf Jelani
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Diagnostic Pathology / Issue 1/2013
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/1746-1596-8-78

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Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family

Abstract

Background

Methods

Results

Conclusion

Virtual Slides

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Virtual Slides

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