Maternally inherited type 2 diabetes mellitus may be associated with mitochondrial tRNAThr mutations

Table 1 Clinical and molecular features of several affected subjects with type 2 diabetes mellitus

Subjects	Sex	Smoking status	BMI (kg/m2)	Age at examination (years)	Age at onset (years)	BP (mmHg)	Ketoacidosis	PTA (left/right) (dB)	Degree of hearing loss	Visual acuity (left/right)	Degree of visual impairment	Functional mtDNA mutations
DM-005: II-4	Female	-	25	79	62	110/70	No	100/90	Profound	0.02/0.05	Severe	tRNAThr G15927A
DM-005: II-6	Female	-	27	74	63	110/70	Yes	85/75	Severe	0.1/0.1	Moderate	tRNAThr G15927A
DM-010: II-1	Male	+	23	72	69	113/86	No	55/20	Mild	0.3/0.2	Mild	tRNAThr G15930A and A15951G
DM-010: II-8	Female	-	21	75	64	130/89	No	66/70	Severe	0.2/0.2	Mild	tRNAThr G15930A and A15951G
DM-010: III-4	Female	+	22	50	48	107/73	Yes	20/15	Normal	0.5/0.5	Normal	tRNAThr G15930A and A15951G

BMI: Body mass index; BP: Blood pressure; dB: Decibel; DM: Diabetes mellitus; mtDNA: Mitochondrial DNA; PTA: Pure-tone average.

Table 2 Laboratory assessments of several affected patients with type 2 diabetes mellitus

Subjects	FBG (mmol/L)	FINS (μU/mL)	HOMA-IR	HbA1c (%)	Serum Cr (µmol/L)	eGFR (mL/min)	LDH (U/L)	ALT (U/L)	AST (U/L)	TC (mmol/L)	LDL-C (mmol/L)	HDL-C (mmol/L)
Normal range	3.9-6.1	2.6-12.0	< 2.69	4.0-6.0	57-111	80-130	50-240	9.0-50	15-40	2.85-5.70	1.31-3.37	0.9-1.95
DM-005: II-4	8.0	31.0	11.02	9.2	122	55	255	16	49	3.58	4.55	0.66
DM-005: II-6	7.5	4.88	1.63	6.9	110	63	268	18	55	3.11	5.10	0.81
DM-010: II-1	7.0	13.90	4.32	7.5	76	95	88	29	22	4.25	3.35	1.37
DM-010: II-8	5.1	10.22	2.32	5.0	68	101	92	33	40	4.9	3.10	1.42
DM-010: III-4	4.8	3.50	0.75	5.6	92	122	105	37	43	5.0	2.9	1.28

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Creatinine; DM: Diabetes mellitus; eGFR: Estimated glomerular filtration rate; FBG: Fasting blood glucose; FINS: Fasting insulin; HbA1c: Hemoglobin A1c; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment of insulin resistance; LDH: Lactate dehydrogenase; LDL: Low-density lipoprotein; TC: Total cholesterol.

Table 3 Mitochondrial DNA variants in two Han Chinese pedigrees with type 2 diabetes mellitus

Genes	Position	Replacement	Conservation (H/B/M/X)1	rCRS	DM-005	DM-010	Previously reported2
D-loop	73	A to G		A	G	G	Yes
	153	A to G		A	G		Yes
	199	A to G		A		G	Yes
	249	Del A		A		Del A	Yes
	263	A to G		A	G		Yes
	310	T to CTC/TC		T	CTC	TC	Yes
	524	Del C		C		Del C	Yes
	16183	T to C		T	C		Yes
	16189	T to C		T		C	Yes
	16311	T to C		T	C		Yes
12S rRNA	709	G to A	G/G/A/-	G		A	Yes
	750	A to G	A/A/A/-	A	G	G	Yes
	1438	A to G	A/A/A/G	A	G	G	Yes
16S rRNA	2706	A to G	A/G/A/A	A	G	G	Yes
	3010	G to A	G/G/A/A	G	A		Yes
	3107	Del N		N	Del N	Del N	Yes
ND1	3552	T to A		T		A	Yes
	3970	C to T		C	T	T	Yes
	4048	G to A (Asp to Asn)		G		A	Yes
	4071	C to T		C	T		Yes
ND2	4715	A to G		A	G		Yes
	4769	A to G		A	G	G	Yes
	4883	C to T		C	T	T	Yes
	5178	C to A (Leu to Met)	L/T/T/T	C	A		Yes
	5460	G to A (Ala to Thr)	A/V/I/I	G	A		Yes
CO1	6053	C to T		C	T		Yes
	6392	T to C		T		C	Yes
	7028	C to T		C	T	T	Yes
	7196	C to A		C		A	Yes
CO2	8020	G to A		G	A		Yes
NC7	8271-8279	9-bp Del			9-bp Del		Yes
A6	8701	A to G (Thr to Ala)	T/S/L/Q	A	G	G	Yes
	8860	A to G (Thr to Ala)	T/A/A/T	A	G	G	Yes
	9053	G to A (Ser to Asp)	S/G/G/T	G	A		Yes
CO3	9540	T to C		T	C	C	Yes
ND3	10310	G to A		G	A		Yes
	10398	A to G (Thr to Ala)	T/T/T/A	A		G	Yes
	10400	C to T		C		T	Yes
ND4	10873	T to C		T		C	Yes
	11719	G to A		G	A	A	Yes
ND5	12705	C to T		C	T	T	Yes
	13928	G to C (Ser to Thr)		G	C		Yes
ND6	14668	C to T		C	T	T	Yes
CytB	14783	T to C		T	C		Yes
	15043	G to A		G	A	A	Yes
	15301	G to A		G	A	A	Yes
	15326	A to G (Thr to Ala)	T/M/I/I	A	G	G	Yes
tRNAThr	15927	G to A	G/G/G/G	G	A		Yes
	15930	G to A	G/G/A/A	G		A	Yes
	15951	A to G	A/A/A/A	A		G	Yes

¹Conservation assessment of mutations in tRNA, rRNA and OXPHOS-encoding genes among human (H), bovine (B), mouse (M), and Xenopus laevis (X).

²Please see the Mitomap (HYPERLINK) and mtDB (HYPERLINK) databases.

DM: Diabetes mellitus; OXPHOS: Oxidative phosphorylation; rCRS: Revised Cambridge Reference Sequence.

Table 4 Molecular characteristics of type 2 diabetes mellitus-associated G15927A, G15930A, and A15951G mutations

Gene	Nucleotide changes	CI (%)	Number of nucleotides in tRNA	Location in tRNA	Watson-Crick base pairing	Disease association
tRNAThr	G15927A	100	42	Anticodon stem	Disrupt 28C-42G base pairing	NSHL; LHON; CHD; DCM
tRNAThr	G15930A	50	45	Variable region	-	NSHL
tRNAThr	A15951G	100	71	Acceptor arm	Disrupts 2T-71A base pairing	LHON

CHD: Coronary heart disease; CI: Conservation index; DCM: Dilated cardiomyopathy; LHON: Leber hereditary optic neuropathy; NSHL: Nonsyndromic hearing loss.