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Identification and characterisation of the familial partial lipodystrophy gene

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thesis
posted on 15.12.2014, 10:38 by David John. Lloyd
Familial partial lipodystrophy (FPLD) is an inherited condition in which regional fat loss occurs at onset of puberty. Additionally, endocrine dysfunctions manifest as insulin resistance and hyperlipidaemia. FPLD is an autosomal dominant disorder and a disease locus has been identified on chromosome 1q21. Through a potential-candidate cloning approach we identified the causative gene. Haplotype analyses were used to refine the disease critical interval to 3.8 cM, between the microsatellite markers D1S2346 and D1S2624. A physical map of the region was constructed and used to position candidate genes. Missense mutations were detected in the LMNA gene in independent FPLD families; all localised to codons 482 and 486, within exon 8. Interestingly, heterozygous mutations have been reported in LMNA in kindreds exhibiting monocyte and cardiomyocyte abnormalities.;The LMNA gene encodes the lamin A/C proteins, components of the nuclear lamina - a meshwork-like structure within the inner nuclear membrane. We speculated that an adipocyte specific interaction exists with lamin A and is perturbed in FPLD subjects. We therefore performed a yeast two-hybrid screen with lamin A as bait to identify adipocyte protein interactions. The most interesting interacting proteins were a group of sterol-regulatory element binding protein (SREBPs) and a group of novel transcripts, hereafter referenced as LIPA. In vitro and in vivo analyses have confirmed these interactions. SREBP is known to be associated with cholesterol and triglyceride biosynthesis and is recognised as an adipogenic transcription factor. Furthermore, transgenic studies leading to overexpression of the nuclear form of SREPB1c resulted in the production of a murine model of lipodystrophy.

History

Date of award

01/01/2001

Author affiliation

Genetics

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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