Type 2 diabetes mellitus may be associated with a novel mitochondrial tRNAThr/tRNAPro mutation

Table 1 Summary of clinical and biochemical data of several matrilineal relatives in this pedigree with type 2 diabetes mellitus

Subjects	Gender	BMI (kg/m2)	Age at onset (year)	Age at test (year)	HbA1c (%)	Glucose (0-hour, mmol/L)	Glucose (2-hour, mmol/L)	Fast insulin (mU/L)	HOMA-IR	TG (mmol/L)	TC (mmol/L)	Serum Cr (μmol/L)	mAlb (mg/L)	α1-mG (mg/L)	eGFR (mL/minute)	BP (mmHg)
II-4	F	23.0	66	72	6.9	7.3	12.6	14.2	4.61	1.22	4.71	122.0	977.2	39.7	69	145/90
II-6	F	22.2	59	63	7.2	7.9	13.5	11.66	4.11	1.09	3.30	139.0	1055.6	47.3	53	155/75
III-4	F	26.2	42	44	6.6	8.8	11.9	7.10	2.79	3.20	5.90	88.0	10.9	9.4	100	155/80
III-10	F	24.3	41	46	6.5	7.2	12.0	6.6	2.11	2.60	2.99	59.0	7.7	8.05	88	140/70
III-9	M	20.5		39	5.2	4.8	7.8	4.2	0.89	1.30	3.48	77.0	6.3	11.1	119	125/75
Normal range		20-22			4.0-6.1	3.9-6.1	3.9-7.8	2.6-12.0	< 2.5	< 1.7	< 5.69	41-81	0-19	0-12.5	80-130	< 140/90

BMI: Body mass index; HbA1c: Glycosylated hemoglobin; HOMA-IR: Homeostatic model assessment for insulin resistance; TG: Triglycerides; TC: Total cholesterol; Cr: Creatinine; mAlb: Microalbumin; α1-mG: Α1-microglobulin; eGFR: Estimated glomerular filtration rate; BP: Blood pressure; F: Female; M: Male.

Table 2 Mitochondrial DNA variants in matrilineal relatives of this type 2 diabetes mellitus pedigree

Gene	Position	Alterations	Amino acid changes	rCRS	Conservation (H/B/M/X)	Reported1
D-loop	73	A to G		A		Yes
	263	A to G		A		Yes
	310	Ins C		T		Yes
	16132	T to C		T		Yes
	16224	T to C		T		Yes
12S rRNA	750	A to G		A	A/A/A/-	Yes
	1107	T to C		T	T/C/T/T	Yes
	1438	A to G		A	A/A/A/G	Yes
16S rRNA	2706	A to G		A	A/G/A/A	Yes
	3107	del N		N	N/T/T/-	Yes
ND1	4200	A to T		A		Yes
	4216	T to C	Tyr to His	T	Y/Y/H/H	Yes
ND2	5178	C to A	Leu to Met	C	L/T/T/T	Yes
CO1	7028	C to T		C		Yes
A6	8414	C to T	Leu to Phe	C	L/F/M/W	Yes
	8584	G to A	Ala to Thr	G	A/V/V/I	Yes
	8701	A to G	Thr to Ala	A	T/S/L/Q	Yes
	8860	A to G	Thr to Ala	A	T/A/A/T	Yes
CO3	9540	T to C		T		Yes
	9545	A to G		A		Yes
ND3	10397	A to G		A		Yes
	10398	A to G	Thr to Ala	A	T/T/T/A	Yes
	10400	C to T		C		Yes
ND4	11722	G to A		G		Yes
	11917	G to A		G		Yes
ND5	12705	C to T		C		Yes
ND6	14318	T to C		T		Yes
	14766	C to T	Thr to Ile	C	T/S/T/S	Yes
CytB	14927	A to G		A		Yes
	15043	G to A		G		Yes
	15301	G to A		G		Yes
	15326	A to G	Thr to Ala	A	T/M/I/I	Yes
tRNAThr/tRNAPro	15954	C to T		C	C/C/C/C	No

¹Please see online MITOMAP (http://www.MITOMAP.org), mtDB (http://www.genpat.uu.se/mtDB) databases.

rCRS: Reversed Cambridge reference sequences; H: Human; B: Bovine; M: Mouse; X: Xenopus laevis; Tyr: Tyrosine; His: Histidine; Leu: Leucine; Met: Methionine; Phe: Phenylalanine; Ala: Alanine; Thr: Threonine; Ile: Isoleucine.

Table 3 The pathogenic role of the m.C15954T mutation

Scoring criteria	m.C15954T mutation	Score/20	Classification
More than one independent report	No	0	≤ 6 points: Neutral polymorphisms; 7-10 points: Possibly pathogenic; 11-13 points (not including evidence from single fiber, steady-state level, or trans-mitochondrial cybrid studies): Probably pathogenic; ≥ 11 points (including evidence from single fiber, steady-state level or trans-mitochondrial cybrid studies): Definitely pathogenic
Evolutionary conservation of the base pair	No changes	2
Variant heteroplasmy	No	0
Segregation of the mutation with disease	Yes	2
Biochemical defect in complex I, III or IV	Yes	2
Evidence of mutation segregation with biochemical defect from single fiber studies	No evidence	0
Mutant mt-tRNA steady-state level or evidence of pathogenicity in trans-mitochondrial cybrid studies	Strong evidence	5
Maximum score	Definitely pathogenic	11

mt: Mitochondrial; tRNA: Transfer RNA.

Table 4 Summary of clinical and molecular data for several Chinese diabetic pedigrees carrying the primary mitochondrial-transfer RNA mutations

Pedigree number	Number of matrilineal relatives	Penetrance of diabetes (%)	mt-tRNA mutations	mtDNA haplogroup	Ref.
1	12	50	tRNAThr/tRNAPro C14954T	F1b1a1	This study
2	11	45.4	tRNAGlu A14687G	G4	Levinger et al[51]
3	11	18.2	tRNAGlu A14692G	B5	Moslemi et al[52]
4	12	41.6	tRNACys/tRNATyr A5826G	D4	Roe et al[41]
5	12	25	tRNALeu(UUR) A3243G	M7c	Jiang et al[17]
6	8	50	tRNAAla T5587C	F2	Brandon et al[15]
7	19	31.5	tRNATrp A5514G	G2a	Crispim et al[53]
8	19	26.3	tRNAThr G15897A	D4b1	Achilli et al[54]
9	11	45.5	tRNAGly T10003C	M11b	Fang et al[55]

mt: Mitochondrial; tRNA: Transfer RNA.