A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy

Joanna Oswiecimska, Mateusz Dawidziuk, Tomasz Gambin, Katarzyna Ziora, Marta Marek, Sylwia Rzonca, D. Lys Guilbride, Shalini N. Jhangiani, Anna Obuchowicz, Alicja Sikora, James R. Lupski, Wojciech Wiszniewski, Pawel Gawlinski

Research output: Contribution to journalArticle

Abstract

Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital generalized lipodystrophy type 1 (CGL1) has not been previously reported. We report the case history of a 27 year old female CGL1 patient presenting with an unusual additional development of non-diabetic peripheral neuropathy and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identified a novel variant, homozygous for a 52 bp intronic deletion in the AGPAT2 locus, coding for 1-acylglycerol-3-phosphate O-acyltransferase 2, which is uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes showed abnormal RNA splicing resulting in the loss of 25 amino acids from the patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced AGPAT2 mRNA in our patient nonetheless remained normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with AGPAT2-associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features associated exclusively with clinical CGL type 2 arising from seipin (BSCL2) gene mutations. This case study suggests that in some genetic contexts, AGPAT2 mutations can also produce phenotypes with primary polyneuropathy.

Original languageEnglish (US)
Pages (from-to)319-326
Number of pages8
JournalJournal of clinical research in pediatric endocrinology
Volume11
Issue number3
DOIs
StatePublished - Sep 3 2019

Fingerprint

Congenital Generalized Lipodystrophy
Polyneuropathies
Mutation
1-Acylglycerol-3-Phosphate O-Acyltransferase
Dual (Psychiatry) Diagnosis
Exome
RNA Splicing
Lipodystrophy
Learning Disorders
Peripheral Nervous System Diseases
Cognition
Proteins
Leukocytes
Genome
RNA
Phenotype
Amino Acids
Messenger RNA

Keywords

  • AGPAT2
  • Berardinelli-Seip syndrome
  • congenital generalized lipodystrophy
  • fat biology
  • polyneuropathy
  • seipinopathy

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy. / Oswiecimska, Joanna; Dawidziuk, Mateusz; Gambin, Tomasz; Ziora, Katarzyna; Marek, Marta; Rzonca, Sylwia; Guilbride, D. Lys; Jhangiani, Shalini N.; Obuchowicz, Anna; Sikora, Alicja; Lupski, James R.; Wiszniewski, Wojciech; Gawlinski, Pawel.

In: Journal of clinical research in pediatric endocrinology, Vol. 11, No. 3, 03.09.2019, p. 319-326.

Research output: Contribution to journalArticle

Oswiecimska, J, Dawidziuk, M, Gambin, T, Ziora, K, Marek, M, Rzonca, S, Guilbride, DL, Jhangiani, SN, Obuchowicz, A, Sikora, A, Lupski, JR, Wiszniewski, W & Gawlinski, P 2019, 'A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy', Journal of clinical research in pediatric endocrinology, vol. 11, no. 3, pp. 319-326. https://doi.org/10.4274/jcrpe.galenos.2018.2018.0227
Oswiecimska, Joanna ; Dawidziuk, Mateusz ; Gambin, Tomasz ; Ziora, Katarzyna ; Marek, Marta ; Rzonca, Sylwia ; Guilbride, D. Lys ; Jhangiani, Shalini N. ; Obuchowicz, Anna ; Sikora, Alicja ; Lupski, James R. ; Wiszniewski, Wojciech ; Gawlinski, Pawel. / A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy. In: Journal of clinical research in pediatric endocrinology. 2019 ; Vol. 11, No. 3. pp. 319-326.
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