ISSN: 1308-5727 | E-ISSN: 1308-5735
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Turkish Society for Pediatric Endocrinology and Diabetes
A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy [J Clin Res Pediatr Endocrinol]
J Clin Res Pediatr Endocrinol. 2019; 11(3): 319-326 | DOI: 10.4274/jcrpe.galenos.2018.2018.0227

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

Joanna Oswiecimska1, Mateusz Dawidziuk2, Tomasz Gambin3, Katarzyna Ziora1, Marta Marek4, Sylwia Rzonca2, D. Lys Guilbride5, Shalini N. Jhangiani6, Anna Obuchowicz4, Alicja Sikora4, James R. Lupski7, Wojciech Wiszniewski8, Pawel Gawlinski2
1Medical University of Silesia in Katowice, Department of Pediatrics in Zabrze, Silesia, Poland
2Institute of Mother and Child, Department of Medical Genetics, Warsaw, Poland
3Institute of Mother and Child, Department of Medical Genetics, Warsaw, Poland & Warsaw University of Technology, Institute of Computer Science, Warsaw, Poland & Baylor College of Medicine, Department of Molecular and Human Genetics, Texas, USA
4Medical University of Silesia in Katowice, Department of Pediatrics in Bytom, Silesia, Poland
5No current affiliation
6Human Genome Sequencing Center, Baylor College of Medicine, Texas, USA
7Baylor College of Medicine, Department of Molecular and Human Genetics, Texas, USA & Human Genome Sequencing Center, Baylor College of Medicine, Texas, USA
8Institute of Mother and Child, Department of Medical Genetics, Warsaw, Poland & Oregon Health and Science University, Department of Molecular and Medical Genetics, Portland, USA

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.

Keywords: Berardinelli-Seip syndrome, seipinopathy, congenital generalized lipodystrophy, polyneuropathy, AGPAT2, fat biology

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. A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy. J Clin Res Pediatr Endocrinol. 2019; 11(3): 319-326
Manuscript Language: English
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