Clinical and Genetic Characteristics of ABCC8 Nonneonatal Diabetes Mellitus: A Systematic Review

Table 2

Variants of ABCC8 causing ABCC8-NNDM reported in previous studies.

Topological domain	Variant (protein effect)	Zygosity	Neurological features	Reference
TMD0	p.S53C, p.V84I, p.E100K	Het		[10, 110, 111]
	p.L171F	Hom		[112]
L0	p.P201S, p.A235T, p.A269D^#, p.G296R^#, p.R306C, p.R306H^#	Het		[15, 16, 32, 111, 113, 114]
TMD1	p.A355T, p.Y356C, p.R370S, p.C418R, p.C435R^#, p.Q485R, p.V563D, p.L582V^#	Het		[10, 15, 23, 27, 111, 113, 115, 116]
NBD1	p.V607M^#, p.R620C, p.G658V, p.D673N, p.N780S, p.R825Q, p.R825W^#, p.G832S, p.Q833K, p.H862R, p.E970V, p.A1536T	Het		[15, 16, 37, 83, 87, 111, 113, 117–120]
TMD2	p.G1008S, p.K1022Q, p.L1147R, p.R1182W^#, p.R1182Q^#, p.P1198L^#, p.E1205K, p.N1244D	Het		[10, 16, 111, 116, 118, 121]
	p.F1067I^#	Hom		[96]
NBD2	p.R1352H, p.A1366T, p.R1379H^#, p.K1384Q, p.S1385F, p.A1390V, p.L1430F, p.Q1458E, p.A1472T, p.G1478R, p.R1493G, p.M1504T, p.E1506K, p.A1507P, p.M1513T, p.V1523L, p.A1536V, p.R1538Q	Het		[1, 10, 14–17, 31, 33, 37, 113, 115, 116, 118, 122–127]
	p.A1457T	Het	Epilepsy	[36]
	p.R1418H, p.R1420H	Hom		[29, 30, 128]
TMD0	p.H103Y + p.R74Q	CH		[35]
L0	p.G214R + p.V222M	CH		[10]
NBD1	p.R933X + c.3992-9G > A, p.F793Sfs71 + c.4608+4A > G	CH		[120, 129]
TMD2	p.L1191LfsX1207 + p.R1250X	CH		[129]
	p.L1147R + p.R1250X	CH		[129]
NBD2	p.R1420H + F591fs604X	CH		[128]

ATP-binding cassette transporter subfamily C member 8 (ABCC8) (accession number: NM_000352.4) has 17 transmembrane helices arranged in groups of five (N-terminal transmembrane domain (TMD0)), six (TMD1), and six (TMD2). Two large cytosolic loops follow TMD1 and TMD2 and contain the nucleotide-binding domains (NBDs, including NBD1 and NBD2) that are characteristic of ATP-binding cassette (ABC) proteins. The L0 linker region is located between the TMD0 and the TMD1 domains. “Neurological features” excludes seizures caused by hypoglycemia. ABCC8-NNDM: ABCC8 variant-induced nonneonatal diabetes mellitus; Het: heterozygous; Hom: homozygous; CH: compound het. indicates that the damaging effect of the variant has been demonstrated in functional studies. # indicates that the variants have been reported to cause ABCC8-NDM and ABCC8-NNDM.