Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

Autor: Hitoshi Shimano, Yoko Sugano, Yuki Yamamoto, Naoya Yahagi, Shigeru Yatoh, Yasuhisa Furuta, Takaaki Matsuda, Motohiro Sekiya, Yuki Murayama, Hiroaki Suzuki, Hitoshi Iwasaki, Mariko Ohyama, Yoshinori Ohsaki
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Glucose Transport Proteins
Facilitative
Organic Anion Transporters
Case Report
Gene mutation
medicine.disease_cause
HNF1A
0302 clinical medicine
Insulin-Secreting Cells
Insulin Secretion
Insulin
Hyperuricemia
Hepatocyte Nuclear Factor 1-alpha
Hypouricemia
Genetics (clinical)
Exome sequencing
Mutation
biology
Homozygote
Whole exome analysis
SLC22A12
Urinary Calculi
medicine.medical_specialty
Heterozygote
lcsh:Internal medicine
Renal Tubular Transport
Inborn Errors
Organic Cation Transport Proteins
lcsh:QH426-470
ABCG2
Diabetes Complications
03 medical and health sciences
Internal medicine
Exome Sequencing
Genetics
medicine
Humans
lcsh:RC31-1245
NKX6.1
Aged
030203 arthritis & rheumatology
Homeodomain Proteins
Impaired insulin secretion
medicine.disease
Uric Acid
lcsh:Genetics
030104 developmental biology
Endocrinology
Glucose
biology.protein
SLC2A9
Zdroj: BMC Medical Genetics, Vol 21, Iss 1, Pp 1-9 (2020)
BMC Medical Genetics
ISSN: 1471-2350
DOI: 10.1186/s12881-020-01031-z
Popis: Background Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic β-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. Case presentation We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8–7.0 mg/dl), 41.6 μmol/l (226–416 μmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 μg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the non-synonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic β-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation. Conclusion We found a case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic β-cell functions that deserve further scrutiny.
Databáze: OpenAIRE
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