Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
10q25.2 | ?Lipodystrophy, familial partial, type 8 | 620679 | Autosomal dominant | 3 | ADRA2A | 104210 |
A number sign (#) is used with this entry because of evidence that familial partial lipodystrophy type 8 (FPLD8) is caused by heterozygous mutation in the ADRA2A gene (104210) on chromosome 10q25. One such family has been reported.
Familial partial lipodystrophy type 8 (FPLD8) is an autosomal dominant disorder characterized by abnormal distribution of subcutaneous adipose tissue. Affected individuals showed selective loss of subcutaneous adipose tissue from the limbs, resulting in a muscular appearance, beginning around 13 to 15 years of age. There is also abnormal accumulation of subcutaneous adipose tissue in the dorsal neck and face, as well as in the posterior thoracic and abdominal regions. The disorder is associated with metabolic abnormalities, including diabetes mellitus and hyperlipidemia (Garg et al., 2016).
For a general description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.
Garg et al. (2016) reported an African American family (FPLD 122) in which a 62-year-old woman and 2 of her sons, 46 and 39 years of age, had onset of atypical partial lipodystrophy around 13 to 15 years of age. They had marked loss of subcutaneous fat and increased muscularity of the upper and lower extremities and excessive fat accumulation in the dorsocervical region, requiring surgical removal of fat in this region in 2 of the patients. Some had accumulation of adipose tissue in the lower face. As adults, all developed diabetes, hypertension, and hyperlipidemia with increased triglycerides. The 46-year-old proband also had acanthosis nigricans, hepatomegaly, elevated creatine kinase, and increased uric acid. Full-body MRI of the brothers showed loss of subcutaneous fat from the scalp, orbits, and anterior truncal region, but preservation of posterior subcutaneous, perirenal, and intraperitoneal fat. Total body fat was reduced in all.
The transmission pattern of FPLD8 in the family reported by Garg et al. (2016) was consistent with autosomal dominant inheritance.
In 3 affected members of an African American family (family FPLD 122) with FPLD8, Garg et al. (2016) identified a heterozygous missense mutation in the ADRA2A gene (L68F; 104210.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two clinically unaffected children (3 and 8 years of age) who were younger than the age of symptom onset also carried the mutation. The mutation was not present in the ExAC or dbSNP databases. Expression of the mutation in HEK293 cells showed that the mutant ADRA2A protein was expressed and localized normally to the plasma membrane, but caused slightly increased cAMP production compared to wildtype. Differentiated adipose cells (3T3-L1) transfected with the mutation had a higher rate of basal lipolysis compared to controls, as evidenced by glycerol release. Synthesis of cAMP and lipolysis in cells carrying the mutation were resistant to suppression by clonidine and not sensitive to yohimbine, suggesting that the mutation results in a loss of function. The findings suggested that excessive lipolysis from certain adipose tissue deposits is the main mechanism causing the disorder.
Garg, A., Sankella, S., Xing, C., Agarwal, A. K. Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy. JCI Insight 1: e86870, 2016. [PubMed: 27376152] [Full Text: https://doi.org/10.1172/jci.insight.86870]