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

Table 1

Variants of ABCC8 causing neonatal diabetes mellitus reported in previous studies.

Topological domain	Variant (protein effect)	Zygosity	Neurological features	Reference
TMD0	p.S8R, p.V86A, p.V86G, p.A90V, p.F132V, p.L135P	Het		[50, 58–63]
	p.I49F, p.F132L	Het	DEND	[39, 50, 58, 59, 64–66]
	p.N72S	Mosaic		[50, 58, 59, 64, 67]
L0	p.E208K, p.D209E, p.D209N, p.Q211K, p.D212E, p.D212N, p.D212Y, p.R216C, p.L225P, p.T229N, p.R285Q, p.G296R	Het		[2, 50, 52, 58, 59, 61, 64, 66, 68–71]
	p.D212I	Het	Muscle hypotonia	[58, 59, 70]
	p.L213P, p.L213R, p.R306H	Het	DEND	[40, 50, 59, 72, 73]
	p.A269D	Het	Hypotonia	[2, 50]
	p.T229I	Hom		[50, 58, 59]
	p.E208K+ p.Y263D	CH	DEND	[58, 59, 64]
TMD1	p.V324M, p.A355T, p.E350D, p.I395F, p.H410Y, p.S459R, p.Q485H, p.F536L, p.F577L, p.I585T	Het		[2, 13, 50, 53, 59, 65, 73–78]
	p.D424V	Het	Seizure	[79]
	p.C435R, p.L451P, p.V587G	Het	DEND	[40, 50, 59, 80, 81]
	p.L582V	Het	Slow ideation	[2, 23, 40, 50, 59]
	p.E382K, p.E382V	Hom		[50, 59, 64, 69, 82]
NBD1	p.V607M, p.R653Q, p.R825W, p.G832C, p.G832D, p.H862Y, p.R877Q, p.D897V, p.E939K	Het		[24, 61, 62, 66, 75, 82–87]
	p.R825W	Het	iDEND	[2, 24, 50, 52, 54, 58, 59, 63, 68–70, 87]
	p.E747X, p.R825W	Hom		[62, 88]
TMD2	p.H1023Y, p.S1053N, p.F1176L, p.Q1178R, p.R1182Q, p.R1182W, p.F1181S, p.P1198L, p.G1255S	Het		[2, 12, 23, 25, 26, 40, 50, 52, 58, 59, 66, 70, 73, 85, 89–95]
	p.N1122D	Het	Seizure	[50, 60]
	p.F1067I	Hom		[96]
	p.H1023R	Hom		[97]
	p.F1163L	Hom	DEND	[69, 82, 98]
	p.A1184E	Hom	Muscle weakness and seizures	[50, 59, 64]
NBD2	p.R1313H, p.R1379S, p.I1424V, p.E1506Q, p.E1506D, p.E1506G, p.V1522M	Het		[2, 13, 26, 40, 50, 58, 59, 76, 89, 99]
	p.R1379H	Het	Hyperkinesia	[2, 50, 59, 70, 80]
	p.R1379C	Het	Minor dystonia	[23, 40, 50, 52, 59, 70, 76, 100]
	p.R1379L	Het	DEND	[50, 58, 59, 100]
	p.A1536P	Het	Motor delay	[101]
L0 + NBD1	p.V215I + V607M, p.L225P + D879N	CH		[58, 102, 103]
L0 + NBD2	p.T229I+ p.V1522L	CH		[58, 59, 64]
L0 + TMD1	p.P207S+ p.Y179X	CH		[59, 64]
NBD1 + TMD0	p.E747X+ p.E128K	CH		[88]
NBD2 + TMD2	p.E1327K+ p.V1523A + T1043QfsX74	CH		[59, 64, 104]
TMD0 + L0	p.A30V + p.G296R	CH		[105]
TMD0 + NBD1	p.N23H+ p.R825W	CH		[63]
TMD0 + NBD2	p.P45L+ p.G1400R	CH	Reduced consciousness, seizures	[58, 59, 64, 106]
	p.L147R + p.R1379C	CH		[107]
TMD0 + TMD2	p.R168C+ p.G1256S	CH		[108, 109]
TMD1 + TMD2	p.V324M + p.R1394L	CH	DEND	[65]
	p.L438F+ p.M1289V, p.I544T+ p.R1214W, p.N426S+ p.R1182Q	CH		[13, 59, 66]
TMD2 + L0	A1263V + I196N	CH		[52]

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. ABCC8-NDM: ABCC8 variant-induced neonatal diabetes mellitus; Het: heterozygous; Hom: homozygous; CH: compound het; DEND: developmental delay and epilepsy syndrome; i-DEND: intermediate DEND syndrome. indicates that the variant has been demonstrated to be activating in functional studies.