Fitting the pieces of the puzzle together: a case report of the Dunnigan-type of familial partial lipodystrophy in the adolescent girl

Krawiec, Paulina; Mełges, Beata; Pac-Kożuchowska, Elżbieta; Mroczkowska-Juchkiewicz, Agnieszka; Czerska, Kamila

doi:10.1186/s12887-016-0581-2

Cited by 12 publications

(8 citation statements)

References 17 publications

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“…A different region of the Ig-fold surface is specifically affected by variants linked to progeria. In particular, atypical HGPS (AHGPS) and MADA, which have overlapping clinical phenotypes ( Guénantin et al, 2014 ; Mehrez and Mostafa, 2014 ; Krawiec et al, 2016 ), are caused by single substitutions at residues R435, R471, R527, A529, M540, or K542, which form a ‘patch’ on the Ig-fold surface (Front views; AHGPS and MADA; Figure 4B ). We exclude neighboring residue T528 as a core component of this ‘progeria patch’ because most T528 variants cause muscular dystrophy ( Vytopil et al, 2003 ; Verstraeten et al, 2006 ; Astejada et al, 2007 ; Bertrand et al, 2011 ; Scharner et al, 2011 ).…”

Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases (‘laminopathies’) including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2), insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations (‘variants’) in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA). We identified 169 variants in the ExAC cohort, of which 37 (∼22%) are disease-associated including p.I299V (allele frequency 0.0402%), p.G602S (allele frequency 0.0262%) and p.R644C (allele frequency 0.124%), suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D) Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58), and was more frequent in African Americans (allele frequency 0.297%). The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%). The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B), p.R397C and p.R427C (predicted to perturb filament biogenesis), p.G638R and p.N660D (predicted to perturb prelamin A processing), and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein–protein interactions. Overall, this two-pronged strategy— mining a large database for missense variants in a single gene (LMNA), coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric disease, identified known variant p.I299V as a potential risk factor for metabolic disease in Latinos, linked variant p.G602 with type 2 diabetes, and identified p.G602S as a predictor of diabetes risk in African Americans.

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Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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“…Single-gene mutations resulting in either congenital generalised or familial partial lipodystrophy are characterised by peripheral insulin resistance due to an absence of subcutaneous adipose tissue, and affected individuals typically develop diabetes in adolescence [ 36 ]. However, birthweights of infants with congenital generalised lipodystrophy have been reported to be normal [ 37 ] and though there are reports of low birthweight in familial partial lipodystrophy [ 38 , 39 ], this has not been widely reported as a typical clinical feature in the literature [ 40 – 42 ].…”

Section: The Fetal Insulin Hypothesis From the Perspective Of Monogenmentioning

confidence: 99%

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

et al. 2021

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In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease. Graphical abstract

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“…Genetic analyses demonstrate missense mutations in the LMNA gene [11], which are associated with defective adipogenesis, premature death of adipocytes, and lipotoxicity [12]. The first report of a mutation in the LMNA gene, located on chromosome 1q21-22, related to FPLD2, in 2000, confirmed the mutation as p.R482Q [11].…”

Section: Diagnosis Of Dunnigan-type Lipodystrophymentioning

confidence: 69%

“…The first report of a mutation in the LMNA gene, located on chromosome 1q21-22, related to FPLD2, in 2000, confirmed the mutation as p.R482Q [11].…”

Section: Diagnosis Of Dunnigan-type Lipodystrophymentioning

confidence: 94%

Dunnigan-Type Familial Partial Lipodystrophy: Understanding and Treating the Syndrome

Santos¹,

Ferreira²,

Benazzi³

et al. 2017

OJEMD

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Dunnigan-type partial lipodystrophy, which is characterized by a number of metabolic alterations, change in body fat distribution, and autosomal dominant inheritance pattern, is rare in the general population. Objective: To report the case of an adolescent with clinical and laboratory findings suggestive of Dunnigan-type partial lipodystrophy. Methods: Case report and literature review. Results: A 15-year-old adolescent presented at the clinic complaining of darkening of skin folds on her trunk and back. During physical examination, the presence of serious acanthosis nigricans in her cervical region, axillae, and intergluteal space was noted. Hirsutism in androgen-dependent areas was also observed, as well as relevant reduction of subcutaneous adipose tissue in the limbs, gluteal region, abdomen, and trunk and fat accumulation in the face and chin. Discussion. Dunnigan-type familial partial lipodystrophy is a rare dominant autosomal disease resulting from a heterozygous missense mutation in the LMNA gene, known as LPF type 2 (Dunnigan variant), which encodes the nuclear protein A/C-type lamin. It is characterized by the progressive disappearance of the subcutaneous adipose tissue in the limbs, gluteal region, abdomen, and trunk, with onset in puberty, followed by fat accumulation in other areas such as the face, chin, labia majora, and intra-abdominal region, leading to hypertrophy that may mimic the Cushing's syndrome phenotype. Affected patients display marked insulin resistance and may consequently develop diabetes mellitus, acanthosis nigricans, hirsutism, and polycystic ovary syndrome. Conclusion: This case report highlights the importance of suspecting Dunnigan-type familial partial lipodystrophy in clinical practice. Early clinical diagnosis allows for measures that minimize the severe metabolic disorders associated with this disease and, consequently, these adolescents' self-esteem issues.

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Fitting the pieces of the puzzle together: a case report of the Dunnigan-type of familial partial lipodystrophy in the adolescent girl

Cited by 12 publications

References 17 publications

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Dunnigan-Type Familial Partial Lipodystrophy: Understanding and Treating the Syndrome

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