The BSCL2 gene provides instructions for making a protein called seipin, whose function is unknown. Within cells, seipin is located in the membrane of a structure called the endoplasmic reticulum. The endoplasmic reticulum modifies newly produced proteins and also helps transport proteins, fats, and other molecules to specific sites either inside or outside the cell.
The BSCL2 gene is active in cells and tissues throughout the body, particularly in nerve cells that control muscle movement (motor neurons) and in the brain. The gene is also active in fat-storing cells called adipocytes, which are the major component of fatty (adipose) tissue. Studies suggest that seipin plays a critical role in the development and function of adipocytes. In particular, seipin is involved in the development of lipid droplets, which are structures within these cells that store fat molecules.
Health Conditions Related to Genetic Changes
MedlinePlus Genetics provides information about Charcot-Marie-Tooth diseaseMore About This Health Condition
Congenital generalized lipodystrophy
At least 25 mutations in the BSCL2 gene have been identified in people with congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 2. This rare condition is characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. In some cases, this form of the condition is also associated with intellectual disability, which is usually mild to moderate.
Most of the BSCL2 gene mutations that cause congenital generalized lipodystrophy type 2 lead to the production of a nonfunctional version of the seipin protein or prevent cells from making any of this protein. A loss of functional seipin disrupts the normal development and function of adipocytes, including lipid droplets, which prevents fats from being stored normally in adipose tissue. The resulting lack of body fat underlies most of the signs and symptoms of congenital generalized lipodystrophy type 2. A loss of seipin function in the brain may help explain why intellectual disability can occur with this form of the condition.More About This Health Condition
Distal hereditary motor neuropathy, type V
At least two BSCL2 gene mutations have been identified in people with distal hereditary motor neuropathy, type V, a progressive disorder that affects motor neurons in the spinal cord. It results in muscle weakness and affects movement of the hands and feet. The mutations that can cause this disorder each change a single protein building block (amino acid) in the seipin protein. In one mutation, the amino acid serine is replaced with the amino leucine at position 90 (written as Ser90Leu or S90L). In another, the amino acid asparagine is replaced with the amino acid serine at protein position 88 (written as Asn88Ser or N88S).
It is unclear how BSCL2 gene mutations cause distal hereditary motor neuropathy, type V. These genetic changes probably alter the structure of seipin, causing it to fold into an incorrect 3-dimensional shape. Research findings indicate that misfolded seipin proteins build up in the endoplasmic reticulum. This accumulation likely damages and kills motor neurons, which leads to muscle weakness.More About This Health Condition
At least two mutations in the BSCL2 gene, the N88S and S90L mutations described above, have been reported to cause Silver syndrome. This condition is characterized by muscle weakness and wasting in the hands and abnormal muscle stiffness (spasticity) in the legs. The mutations likely result in misfolded seipin proteins that accumulate within neurons, leading to cell damage and cell death. The loss of neurons causes muscle weakness and spasticity in people with Silver syndrome.
It is unclear how the same mutations in the BSCL2 gene can cause Silver syndrome; distal hereditary motor neuropathy, type V; or another disorder called Charcot-Marie-Tooth syndrome in different people. People with Silver syndrome sometimes have family members with the same BSCL2 gene mutation who have one of these other conditions.More About This Health Condition
Other Names for This Gene
- Berardinelli-Seip congenital lipodystrophy 2 (seipin)
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Auer-Grumbach M, Schlotter-Weigel B, Lochmüller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C; Austrian Peripheral Neuropathy Study Group. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005 Mar;57(3):415-24. Citation on PubMed
- Bienfait HM, Baas F, Koelman JH, de Haan RJ, van Engelen BG, Gabreëls-Festen AA, Ongerboer de Visser BW, Meggouh F, Weterman MA, De Jonghe P, Timmerman V, de Visser M. Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology. 2007 May 15;68(20):1658-67. Citation on PubMed
- Bird TD. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. 1998 Sep 28 [updated 2021 May 20]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from http://www.ncbi.nlm.nih.gov/books/NBK1358/ Citation on PubMed
- Cartwright BR, Binns DD, Hilton CL, Han S, Gao Q, Goodman JM. Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology. Mol Biol Cell. 2015 Feb 15;26(4):726-39. doi: 10.1091/mbc.E14-08-1303. Epub 2014 Dec 24. Citation on PubMed or Free article on PubMed Central
- Cartwright BR, Goodman JM. Seipin: from human disease to molecular mechanism. J Lipid Res. 2012 Jun;53(6):1042-55. doi: 10.1194/jlr.R023754. Epub 2012 Apr 2. Review. Citation on PubMed or Free article on PubMed Central
- Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain. 2009 Jan;132(Pt 1):8-15. doi: 10.1093/brain/awn216. Epub 2008 Sep 12. Review. Citation on PubMed
- Ito D. BSCL2-Related Neurologic Disorders/Seipinopathy. 2005 Dec 6 [updated 2018 May 24]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from http://www.ncbi.nlm.nih.gov/books/NBK1307/ Citation on PubMed
- Magré J, Delépine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L, Sobel E, Papp J, Meier M, Mégarbané A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J; BSCL Working Group. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001 Aug;28(4):365-70. Citation on PubMed
- Rohkamm B, Reilly MM, Lochmüller H, Schlotter-Weigel B, Barisic N, Schöls L, Nicholson G, Pareyson D, Laurà M, Janecke AR, Miltenberger-Miltenyi G, John E, Fischer C, Grill F, Wakeling W, Davis M, Pieber TR, Auer-Grumbach M. Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome. J Neurol Sci. 2007 Dec 15;263(1-2):100-6. Epub 2007 Jul 30. Citation on PubMed or Free article on PubMed Central
- Wee K, Yang W, Sugii S, Han W. Towards a mechanistic understanding of lipodystrophy and seipin functions. Biosci Rep. 2014 Oct 2;34(5). pii: e00141. doi: 10.1042/BSR20140114. Review. Citation on PubMed or Free article on PubMed Central
- Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004 Mar;36(3):271-6. Epub 2004 Feb 22. Citation on PubMed