OMIM: Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia
Monogenic form of diabetes caused by mutations in AGPAT2 (PMID:21127150)
Three major criteria or two major criteria plus two or more minor criteria make a diagnosis of BSCL very likely....
DiagnosisClinical DiagnosisThree major criteria or two major criteria plus two or more minor criteria make a diagnosis of BSCL very likely.Major criteriaLipoatrophy affecting the trunk, limbs, and face. Generalized lipodystrophy is apparent at birth. In some individuals, the face may be normal at birth with lipoatrophy becoming apparent during the first months of life. Lipoatrophy gives an athletic appearance, especially because skeletal muscle hypertrophy is also present.Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in the male.Hepatomegaly. Liver enlargement is secondary to fatty liver early on and to cirrhosis late in the disease course.Elevated serum concentration of triglycerides. Serum concentration of triglycerides can be elevated up to 80 g/L, and is sometimes associated with hypercholesterolemia.Insulin resistance. Elevated serum concentrations of insulin and C-peptide may occur starting in the first years of life. Overt clinical diabetes mellitus usually develops during the second decade. Its early clinical expression is acanthosis nigricans of the groin, neck, and axillae, which may have, in some cases, a verrucous appearance.Minor criteriaHypertrophic cardiomyopathy may be present in infancy or develop later in life.Psychomotor retardation or mild (IQ 50-70) to moderate (IQ 35-50) intellectual impairment. Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.Hirsutism manifests with low frontal and posterior hairline; hypertrichosis is apparently independent of hormonal stimulation.Precocious puberty in females. In a series of 75 individuals with BSCL, three females underwent puberty before age seven years [Van Maldergem et al 2002]. Bone cysts occur in 8%-20% of affected individuals and have a polycystic appearance on x-ray. Located in the epiphyseal and metaphyseal regions of the long bones, bone cysts are often diagnosed during the second decade and are mostly observed in individuals with mutations in AGPAT2.Phlebomegaly. Prominence of the veins of the lower and upper limbs is observed, in part because of the lack of subcutaneous fat.Molecular Genetic TestingGenes. AGPAT2 and BSCL2, the two genes in which mutations are known to cause Berardinelli-Seip congenital lipodystrophy, are thought to account for 95% of cases of congenital generalized lipodystrophy [Boutet et al 2009]:AGPAT2, associated with BSCL type 1BSCL2, associated with BSCL type 2Evidence for locus heterogeneity. Magré et al [2003] found that 92/94 affected individuals harbor mutations that are either in BSCL2 or AGPAT2 or appear to be linked to their loci; Agarwal et al [2004] found this to be the case in 44/47 affected persons. Recent reports provide evidence for at least two additional loci associated with congenital generalized lipodystrophy and other findings, CGL3 and CGL4, resulting from mutations in CAV1 and PTRF respectively (see Differential Diagnosis) [Kim et al 2008, Simha et al 2008, Hayashi et al 2009].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Berardinelli-Seip Congenital LipodystrophyView in own windowProportion of All BSCLGene SymbolTest MethodMutations DetectedTest AvailabilitySee footnote 1BSCL2Sequence analysisSequence variants 2, 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsSee footnote 5AGPAT2Sequence analysisSequence variants 2Clinical1. The proportion of BSCL caused by mutations in each of the two genes is closely related to the population under study:• BSCL2 disease-causing mutations account for the majority of cases in the Berardinelli-Seip study group [Van Maldergem et al 2002, Magré et al 2003] in which affected individuals originated mostly from Europe, the Middle East, and sub-Saharan Africa; studies from Brazil draw similar conclusions (18/26) [Fu et al 2004, Miranda et al 2009]; likewise, in a small sample from Japan, three of four affected individuals were homozygous for a BSCL2 mutation [Ebihara et al 2004]. • AGPAT2 disease-causing mutations accounted for the majority of affected individuals (26/45) in a study from the US [Agarwal et al 2003]. Of note, many individuals in this cohort are of African ancestry.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. BSCL2 frameshift mutation c.315_319delGTATC is identified in the Lebanese population [Magré et al 2001]. Other mutations are identified in individuals of European, Middle-Eastern, Asian, or Portuguese ancestry.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Nearly all individuals of African origin with BSCL type 1 have the AGPAT2 c.493-2A>G mutation. Other mutations have now been described worldwide in diverse populations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. The diagnosis is established by clinical findings and confirmed with molecular genetic testing.In individuals with intellectual disability or cardiomyopathy, sequencing of BSCL2 should be considered first.The order of molecular genetic testing may also be stratified by the ethnicity of the affected individual (see Table 1, footnotes 1 and 5).Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersAGPAT2. No other phenotypes are associated with mutations in AGPAT2, assuming that Brunzell syndrome is classic BSCL with one of its late complications: bone cysts.BSCL2. Heterozygous missense mutations in BSCL2 have been identified in BSCL2-related neurologic disorders, a spectrum of conditions that includes: Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy type V, spastic paraplegia 17, and Silver syndrome [Windpassinger et al 2004]. The clinical features of these BSCL2-related neurologic disorders include:Onset of symptoms ranging from the first to the seventh decade (6-66 years, mean 19 years)Slow disease progressionUpper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responsesLower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and interosseus dorsalis I muscles) that is frequently unilateralUsually normal sensation except for pallesthesia (i.e., abnormal vibration sense)Pes cavus and other foot deformities
Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals with BSCL. Skeletal muscle hypertrophy occurs in all affected individuals....
Natural HistoryBerardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals with BSCL. Skeletal muscle hypertrophy occurs in all affected individuals.Affected individuals develop insulin resistance and approximately 25%-35% of individuals develop diabetes mellitus between ages 15 and 20 years. Diabetes mellitus can be difficult to control.Hypertrophic cardiomyopathy is reported in 20%-25% of individuals and is a significant cause of morbidity from cardiac failure and early mortality around age 30 years. Affected individuals have died as early as age 19 months of complications of cardiomyopathy.Intellectual impairment is common, especially in individuals with mutations in BSCL2. Intrafamilial variability, including variability in intellectual impairment, exists.Neonatal or infantile presentation. Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All children with the neonatal or infantile presentation demonstrate lipoatrophy in the first year of life. Recently, two children (one of Chinese and the other of Turkish ancestry) came to medical attention in the first year of life with cardiac failure associated with hypertrophic cardiomyopathy [Friguls et al 2009; De Vroede, personal communication]. Homozygous missense mutations were identified in both. Additional reports are required to confirm the existence of a phenotype that presents with cardiac manifestations. A third patient [Debray et al, submitted] confirms the existence of a CGL1 endophenotype comprising early-onset hypertrophic cardiomyopathy. Juvenile presentation. Diabetes mellitus manifest by weight loss, polydipsia, polyuria, or asthenia is frequently the presenting finding in the second decade.Adult presentation. BSCL presents on occasion in early adulthood with diabetes mellitus. Individuals may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly. Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.
Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment....
Genotype-Phenotype CorrelationsApproximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.No correlation exists between the site and type of BSCL2 mutation and intellectual impairment [Van Maldergem et al 2002]. Furthermore, related and unrelated individuals with the same mutation may be discordant for intellectual impairment.Individuals with BSCL2 mutations have increased prevalence of cardiomyopathy.There appears to be no relationship between the site and type of AGPAT2 mutations and severity of lipodystrophy or metabolic complications.
Differential DiagnosisTable 2. OMIM Phenotypic Series: Lipodystrophy, Congenital GeneralizedView in own windowPhenotypePhenotype OMIM numberGene/LocusGene/Locus OMIM numberLipodystrophy, congenital generalized, type 1 608594 AGPAT2, LPAAB, BSCL, BSCL1 603100 Lipodystrophy, congenital generalized, type 2 269700 BSCL2, SPG17, HMN5 606158 Lipodystrophy, congenital generalized, type 3 612526 CAV1, BSCL3, CGL3 601047 Lipodystrophy, congenital generalized, type 4 613327 PTRF, CAVIN, CGL4 603198 From Online Mendelian Inheritance in ManCongenital generalized lipodystrohy 3 (CGL3). Individuals with this condition typically have serum creatine kinase concentrations between 2.5 to ten times the upper limit of normal in addition to features resembling classic BSCL [Kim et al 2008]. Two sibs of Hispanic ancestry with a homozygous CAV1 missense mutation who have hypotonia, elevated serum creatine kinase, atlas-axis instability, and generalized lipodystrophy have been described [Simha et al 2008]. Congenital generalized lipodystrohy 4 (CGL4). Generalized lipodystrophy, distal myopathy, muscular hypertrophy, hypertriglyceridemia, insulin resistance, elevated serum creatine kinase concentration, and normal intelligence were described in five Japanese individuals with mutations in PTRF, encoding polymerase I and transcript release factor of caveloe [Hayashi et al 2009]. A series of affected individuals with cardiac arrhythmia originating from Oman and the UK were reported by Rajab et al [2010]. The PTRF caveolar-associated protein is thought to play an essential role in the formation of caveloe (invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction) and the stabilization of caveolins, proteins present in the caveloe. These new data confirm caveolin deficiency as a cause of the lipodystrophic process.Further diagnoses to consider include the following:In infancySHORT syndrome (OMIM 269880)Neonatal progeroid syndrome (OMIM 264090)Neurometabolic lysosomal storage disorder: Gaucher type 2, Krabbe diseaseRussell diencephalic syndromeLeprechaunism: Donohue syndrome (OMIM 246200)In childhoodFamilial partial Dunnigan-Koëberling lipodystrophy (OMIM 151660)Rabson-Mendenhall syndrome (OMIM 262190)Insulin-dependent diabetes mellitusAcquired generalized lipodystrophy (Lawrence syndrome) [Misra & Garg 2003]. Three subtypes exist.Mandibuloacral dysplasia (MAD) caused by LMNA/C and ZMPSTE24 mutationsHutchinson-Gilford progeria syndrome In adulthoodAcquired partial lipodystrophy (Barraquer-Simons syndrome)Lipodystrophy associated with human immunodeficiency virus infectionPartial lipodystrophy with C3 nephritic factorAcquired generalized lipodystrophy (Lawrence syndrome)Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).BSCL type 1 BSCL type 2
To establish the extent of disease in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:Assessment of pubertal status according to Tanner's chartsNeurologic examinationSearch for signs of liver and muscle dysfunctionSearch for evidence of hypertrophic cardiomyopathySearch for evidence of possible orthopedic problems (reduced hip mobility, genu valgum)Complete ophthalmologic examination, including slit lamp examinationTesting of cognitive ability with age-appropriate scalesThe following additional investigations are recommended:Complete blood countSerum concentration of creatine kinaseSerum concentration of electrolytes, insulin, AST, alanine transaminase, urea, creatinine, C-peptide, triglycerides, cholesterolSerum proteins and electrophoresisOral glucose tolerance test. When appropriate: clamp glucose homeostasis studyWhen appropriate: GH, IgG, A, M, E, C3 nephritic factor, CH50, C3, C4 apolipoproteins, hypothalamo-pituitary dynamic testsEchocardiogramWhole-body MRI to determine possible residual mechanical “brown” adipose tissue, which is present in CGL1, but not CGL2 [Simha & Garg 2003] Liver ultrasound examinationRenal ultrasound examination to evaluate for kidney sizeSkeletal survey, especially long bones; search for bone cysts and evaluation of bone age maturationDual energy x-ray absorptiometry (DEXA) scan for assessment of bone density to evaluate for osteopeniaMedical genetics consultationTreatment of ManifestationsRestriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [Garg et al 1999, Beltrand et al 2007, Ebihara et al 2007], but its availability outside of clinical trials remains limited [Simha et al 2002]. A major industrial pharmaceutical company is developing a commercial form of leptin which may become available as early as 2013. Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.Special education is required for individuals with psychomotor retardation or intellectual disability.Prevention of Primary ManifestationsDietary restriction of total fat intake may prevent hypertriglyceridemia (see Treatment of Manifestations). SurveillanceThe following are appropriate:Screening for glycosuria as a manifestation of diabetes mellitusFor individuals with diabetes mellitus, follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complicationsYearly cardiac ultrasound and EKGYearly liver ultrasound examination to detect fatty infiltrationAgents/Circumstances to AvoidExcessive dietary fat intake should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAffected pregnant women should be followed in a high-risk pregnancy care unit by a multidisciplinary team including a specialist in fetal medicine and an expert in diabetic management. Pregnancy may increase the risk of diabetic decompensation. Babies born to women with diabetes are at an increased risk for fetal anomalies and postnatal complications compared to babies born to women without diabetes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherOther drugs, including fenfluramine, have no proven efficacy and should be avoided.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Berardinelli-Seip Congenital Lipodystrophy: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDBSCL1AGPAT29q34.31-acyl-sn-glycerol-3-phosphate acyltransferase betaAGPAT2 homepage - Mendelian genesAGPAT2BSCL2BSCL211q12.3SeipinIPN Mutations, BSCL2 HSP mutation database BSCL2 homepage - Leiden Muscular Dystrophy pages BSCL2 homepage - Mendelian genesBSCL2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Berardinelli-Seip Congenital Lipodystrophy (View All in OMIM) View in own window 269700LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2; CGL2 6031001-@ACYLGLYCEROL-3-PHOSPHATE O-ACYLTRANSFERASE 2; AGPAT2 606158BSCL2 GENE; BSCL2 608594LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 1; CGL1Molecular Genetic PathogenesisWhile little is known on the precise function of seipin, the role of AGPAT2 (1-acyl-sn-glycerol-3-phosphate acyltransferase beta) as a key enzyme in the biosynthesis of triglycerides is well established. Seipin is predicted to be a membrane protein with two transmembrane domains between residues 31-53 and residues 230-252. Studies using confocal analysis and density subcellular fractionation revealed that seipin is mainly located in endoplasmic reticulum (ER). The proteinase K assay demonstrated that seipin is an ER membrane-resident protein with a luminal loop domain and with both termini facing the cytoplasm [Cartwright & Goodman 2012]. It was initially thought that seipin acted as a transcription factor important for stem cell differentiation. Interspecies comparisons indicate a highly conserved region spanning the first 280 amino acids, based on the first reported length of 398 amino acids. Within this region an N-terminal CSSS sequence, present in virtually all species, has been postulated to be implicated in a putative interaction with another molecule. Interestingly, the possible leucine zipper domain contained in the first 280 amino acids of the protein, based on motif searches, is very similar to that contained in the sterol element-binding proteins (SREBPs) which are also located in the endoplasmic reticulum (ER) and also have two transmembrane domains. The latter are transcription factors with a role in regulation of cholesterol biosynthesis and uptake. Study of yeast seipin indicates that it is located at the junction of ER and lipid droplets called adiposomes. When seipin is absent, irregularly shaped small lipid droplets replace these well-formed adiposomes. These findings argue for a direct implication in formation or maintenance of these lipid-containing vesicles. In support of a key role for seipin as an adipogenic transcription factor, it was shown in a knockdown mouse model that synthesis of AGPAT2 and DGAT2 are strongly reduced [Ito & Suzuki 2009]. In keeping with this hypothesis, a series of knockdown experiments conducted in vitro by a British group using small hairpin RNA (shRNA) indicated a failure to induce the lipogenic enzymes AGPAT2 and DGAT2. Interference with some adipogenic transcription factors including peroxisome proliferator-activated receptor (PPAR-gamma) and CAAT/enhancer binding protein-alpha was also observed, as if seipin were located upstream in the metabolic pathway. However, a low expression of seipin in adipose tissue could point to an action through secretory factors [Payne et al 2008]. Moreover, a significant reduction of the expression of major genes involved in triglyceride biosynthesis, namely AGPAT2, lipin 1, and DGAT2, is observed in the knockdown experiments. Lipid accumulation is also inhibited. Interestingly, both BSCL2 nonsense mutations (frequent) and missense mutations (rare) observed in humans have been modeled by Payne et al [2008]. The p.Ala212Pro mutant protein encoded by a missense mutation, observed in a cluster of affected individuals from Norway initially described by Seip in the late 1950s, has been studied. Based on mRNA quantification, BSCL2 protein western blotting studies, and immunolocalization studies, the authors concluded that the p.Ala212Pro mutant protein resulted in mislocalization of adiposomes at the junction of nuclear membrane and ER, while the p.Arg275X mutant protein gave rise to the appearance of the above-described misshapen lipid droplets in their orthotopic ER localization [Payne et al 2008]. This putative adipogenic role of seipin would not give, at first glance, an explanation for the mental impairment often observed in individuals with BSCL. AGPAT2Normal allelic variants. AGPAT2 consists of six exons spanning less than 20 kb.Pathologic allelic variants. Homozygous or compound heterozygous AGPAT2 mutations are associated with BSCL. Agarwal et al [2002] identified various AGPAT2 mutations in 11 pedigrees, including a deletion resulting in a frameshift mutation and premature termination codon, nonsense mutations, splice site mutations, missense mutations, and single amino-acid deletions. Magré et al [2003] also reported various mutations in 38 individuals from 30 pedigrees (for more information, see databases in Table A).Table 3. Selected AGPAT2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.183-2A>G (c.IVS1-2A>G) 2--NM_006412.3 NP_006403.2c.182+1G>A (c.IVS1+1G>A)--c.194G>Ap.Trp65Xc202C>Tp.Arg68Xc.299G>Ap.Ser100Asnc.335C>Tp.Pro112Leuc.492+1G>A (c.IVS3+1G>A)--c.493-1G>C (c.IVS3-1G>C) 2 --c.493-2A>G (IVS4-2A>G) --c.317_588del (c.del317_588) 2p.Leu107Alafs*279c.514G>Ap.Glu172Lysc.538delG (c.del538G)p.Asp180Thrfs*73c.589-2A>G (c.IVS4-2A>G) 2--c.646A>Tp.Lys216Xc.661+2T>G (c.IVS5+2T>G)--c.676C>Tp.Gln226Xc.713C>Gp.Ala238Glyc.755_763del (c.del755_764) p.Met252_Thr254delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Recurrent mutationNormal gene product. The AGPAT2 protein, 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (also known as lysophosphatidic acid acyltransferase beta [LPAAT]), has 278 amino acids and belongs to the family of acyltransferases. The AGPAT2 enzyme catalyzes an essential reaction in the biosynthetic pathway of glycerophospholipids and triacylglycerol [Agarwal et al 2002].Abnormal gene product. Mutations in AGPAT2 may cause congenital lipodystrophy by inhibiting/reducing triacylglycerol synthesis and storage in adipocytes. It is also likely that reduced AGPAT2 activity could increase tissue levels of lysophosphatidic acid, which may negatively affect adipocyte functions [Agarwal et al 2002].BSCL2Normal allelic variants. BSCL2 consists of 11 exons spanning at least 14 kb. The putative translation initiation codon is located in the second exon.Pathologic allelic variants. Homozygous or compound heterozygous BSCL2 mutations are associated with BSCL. Magré et al [2001] identified several different mutations in BSCL2 among 44 individuals, including microdeletions, small insertions and deletions, and five nucleotide substitutions. The majority of mutations resulted in a frameshift or a premature stop codon (for more information, see databases in Table A).Table 4. Selected BSCL2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.142C>Tp.Leu48PheNM_032667.5 NP_116056.3c.154_155dup (c.500_502insTT)p.Tyr53Serfs*40c.194delCinsGGA (c.537_538delCinsGGA)p.Pro65Argfs*28c.315_319delGTATC (c.del659_663)p.Tyr106Cysfs*6c.325dupA (c.324_325 insA)p.Thr109Asnfs*5c.412C>T 2p.Arg138Xc.574-2A>G (c.IVS5-2A>G)--c.672-3C>G (c.IVS6-3C>G)--c.672-2A>C (c.IVS6-2 A>C)--c.672-2A>G (c.IVS6-2A>G)--c.671+5G>A (c.IVS6+5G>A)--c.634G>Cp.Ala212Proc.782dupG (c.1126_1127insG)p.Ile262Hisfs*12c.823C>Tp.Arg275XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Recurrent mutationNormal gene product. BSCL2 encodes a 398 amino-acid protein, seipin (isoform 2, NP_116056.3). Seipin has at least two hydrophobic amino acid stretches, indicating that it could be a transmembrane protein. The function of seipin is unknown [Magré et al 2001]. Seipin also occurs as another isoform. BSCL2 also encodes a protein of 462 amino acids (isoform 1, NP_001116427.1) (versus 398 amino acids reported in the seminal paper); the 398-amino acid-based numbering is still used in order to avoid inconsistencies linked to re-numbering. Seipin is composed of 11 exons and has no significant homology to other known proteins. Multiple seipin transcripts of 1.8, 2.0 and 2.4 kb have been identified by RNA blot analysis. The 1.8- and 2.4-kb transcripts are ubiquitous whereas the 2.0 kb is expressed selectively and at high levels in brain and testis. It has been postulated that this distribution could account for the intellectual disability, voracious appetite, and macrogenitosomia observed in BSCL type 2.Abnormal gene product. The majority of BSCL2 variants are null mutations that are predicted to result in severe disruption of the protein function.