Loss-of-function mutations in the BSCL2
gene cause a severe form of lipodystrophy, whilst characteristic gain-of-function mutations are believed to be associated with aggregation of unfolded protein in endoplasmic reticulum resulting in neurodegeneration leading to a heterogeneous group of neuropathies [5
]. The study presented here was a four generations consanguineous family, originated from Peshawar city Pakistan. Clinical features of the affected individuals resembled CGL2 phenotype. Moreover the first degree consanguinity of the parents and autosomal recessive mode of inheritance of the disease phenotype was a definite clue for a homozygous mutation. Mutations in BSCL2
leading to CGL2 phenotype have been identified worldwide [5
The generalized loss of adipose tissue, increased triglyceride levels and steatosis of the liver were comparable to a homozygous mutation p.Tyr213ThrfsX20 identified in an Indian family [5
]. Early onset diabetes mellitus present in our patients were comparable with homozygous nonsense mutations identified in Chinese and severe insulin resistance in Japanese and Brazilian patients [9
], however we did not perform the insulin resistance test in our patients. The hypertrophic cardiomyopathy identified in our cases was less severe as compared to Chinese patient caused by homozygous nonsense mutation [17
]. There was mild mental retardation (IQ score 65–75) in both of our patients but the brain MRI did not reveal brain atrophy.
The variable features of neuropathies are mostly associated with heterozygous mutations in BSCL2
dHMN, Charcot-Marie-Tooth (CMT) and Silver syndromes [16
]. In 2005, based on disease allele penetrance and severity of phenotype caused by heterozygous mutations in BSCL2
gene p.N88S in Austrian and German families, these patients were classified into six subclinical groups with overlapping features of HMN, CMT and Silver syndrome [20
]. However, in 2009, Brusse et al
. discovered a digenic inheritance of hereditary motor neuropathy in a large Dutch family with heterozygous mutation p.N88S in the BSCL2
gene and segregating autosomal dominant disease haplotype at chromosome 16p [21
]. The phenotypic variability ranged from strictly neuropathic weakness to a spastic paraplegia with hereditary motor neuropathy presenting clinical phenotype similar to Silver syndrome [21
]. Very recently another heterozygous mutation p.S90W identified in two Korean CMT type 2 disease patients [22
] was associated with increased density of myelinated fibers. However, this feature was slightly different from the previously reported mutation p.S90L in three Italian patients representing CMT type 2 phenotype with pyramidal signs and subclinical sensory involvement on sural nerve biopsy [23
gene encodes 398 or 462 amino acids seipin protein from either of the three transcripts 1.6 kb, 1.8 kb and 2.2 kb [24
]. The 1.8 kb transcript is exclusively expressed in brain and testis while the other two are ubiquitously expressed [18
]. Seipin protein is located in endoplasmic reticulum acting as a regulator of lipid catabolism and is essential for the differentiation of fat cells [18
]. Studies have revealed role of seipin in proper lipid storage and regulation of cAMP/PKA-mediated lipolysis in adipose differentiation [25
]. In adult mice brain bscl2
expression studies have suggested the possible involvement of seipin in central regulation of energy balance.
According to UniprotKB database (http://www.uniprot.org/uniprot/Q96G97
), 398 amino acids seipin protein has five domains including 2 cytoplasmic [1-26aa and 264-398aa], 2 transmembrane [27-47aa and 243-263aa] and a luminal [48-242aa]. So far 31 mutations are reported in BSCL2
gene including 12 missense/nonsense, 4 small insertions, 4 small deletions, 7 splice-site mutations and 4 complex rearrangements causing related phenotypes as summarized in Table .
List of mutations in BSCL2 gene so far
More than three hundred cases of BSCL have been reported in the medical literature with an estimated prevalence of 1 in 10 million people in USA [35
]. However this condition is more common in other populations around the world like Lebanon, Brazil, Portugal and Sultanate of Oman with an estimated prevalence of 1:25000 to 1:1000000 [36
]. The incidence data of BSCL and many other rare disorders are not available from Pakistan partly due to lack of disease registry database systems and non-availability of neonatal screening programs in the hospitals.
Generally, in families segregating autosomal recessive disorders, high frequency of consanguineous marriages may increase the frequency of homozygotes in the population leading to increased incidence of certain lesions, their founder effect and also the appearance of new mutations [37
]. Although most causative mutations in Mendelian diseases are reported in single families, certain mutations may occur more frequently in some populations than others. Few examples of such prevalent mutations may be observed in Wilson’s disease [38
], hemophilia [39
], Hurler disease [37
] and thalassemia [40
]. Knowledge of the differences in the worldwide distribution of particular mutations may help to design shortcuts for genetic diagnosis and screening of relevant inherited diseases.