Maternally Inherited Essential Hypertension May Be Associated with the Mutations in Mitochondrial tRNA^Glu Gene

Figures & data

Figure 1 Two Han Chinese families with EH, arrows indicate the probands.

Table 1 Summary of Clinical Data for Some Members in Two Families with EH

Subjects	Gender	Age at Test	Age at Onset	Diastolic BP (mmHg)	Systolic BP (mmHg)
II-6 (Family 1)	Female	75	70	100	150
II-8 (Family 1)	Female	72	69	90	145
III-3 (Family 1)	Female	50	48	95	130
III-10 (Family 1)	Female	45	41	90	160
I-2 (Family 2)	Female	88	71	95	145
II-6 (Family 2)	Female	66	60	100	180
III-4 (Family 2)	Female	40	35	90	155

Abbreviation: BP, blood pressure.

Table 2 mtDNA Sequence Variations in Two Families with EH

Gene	Position	Replacement	Conservation (H/B/M/X)^a	rCRS^b	Family 1	Family 2	Previously Reported^c
D-loop	73	A to G		A	G	G	Yes
	146	T to C		T	C		Yes
	150	C to T		C		T	Yes
	195	T to C		T	C	C	Yes
	263	A to G		A	G	G	Yes
	310	T to C		T	C		Yes
	489	T to C		T	C	C	Yes
	524	Del C		C		Del C	Yes
	573	C to CCC		C	CCC		Yes
	16,189	T to C		T	C	C	Yes
	16,223	C to T		C	T	T	Yes
	16,304	T to C		T	C		Yes
	16,362	T to C		T		C	Yes
	16,519	T to C		T	C		Yes
12S rRNA	709	G to A	G/G/A/-	G		A	Yes
	750	A to G	A/G/G/-	A	G	G	Yes
	1107	T to C	T/C/T/T	T		C	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		Yes
ND1	3348	A to G		A	G		Yes
	3970	C to T		C	T	T	Yes
ND2	4685	A to G		A	G		Yes
	4769	A to G		A		G	Yes
	4883	C to T		C		T	Yes
	4924	G to A (Ser to Asn)	S/N/T/P	G	A		Yes
	4985	G to A		G		A	Yes
	5178	C to A (Leu to Met)	L/T/T/T	C		A	Yes
	5301	A to G		A	G		Yes
CO1	6026	G to A		G		A	Yes
	6284	A to G		A	G		Yes
	7028	C to T		C	T	T	Yes
	7196	C to A		C	A		Yes
CO2	7768	A to G		A	G	G	Yes
	8020	G to A		G	A		Yes
A8	8414	C to T (Leu to Phe)	L/F/M/W	C		T	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
	8964	C to T		C		T	Yes
CO3	9327	A to G (Thr to Ala)	T/T/T/I	A	G		Yes
	9540	T to C		T	C	C	Yes
	9950	T to C		T		C	Yes
ND3	10,398	A to G (Thr to Ala)	T/T/T/A	A	G		Yes
	10,400	C to T		C	T		Yes
ND4	10,873	T to C		T	C	C	Yes
	11,719	G to A		G	A	A	Yes
ND5	12,705	C to T		C	T		Yes
	13,708	G to A (Ala to Thr)	A/L/A/A	G		A	Yes
	13,928	G to C (Ser to Thr)	S/T/S/T	G	C		Yes
ND6	14,455	C to T		C		T	Yes
tRNA^Glu	14,693	A to G	A/A/A/A	A	G		Yes
	14,696	A to G	A/A/A/A	A		G	Yes
CytB	14766	C to T (Thr to Ile)	T/S/T/S	C	T	T	Yes
	15,301	G to A		G		A	Yes
	15,326	A to G (Thr to Ala)	T/M/I/I	A	G	G	Yes
	15,508	C to T		C		T	Yes
	15,851	A to G (Ile to Val)	I/A/S/M	A		G	Yes

Notes: ^aConservation of amino acid for polypeptide or nucleotide for rRNAs in human (H), bovine (B), mouse (M), and Xenopus laevis (X). ^brCRS: revised Cambridge Reference Sequences. ^cSee the online mitochondrial genome database http://www.mitomap.org.

Figure 2 Identification of tRNA^Glu A14693G and A14696G mutations by direct sequencing.

Abbreviations: MT, mutant; WT, wild type.

Figure 3 Secondary structure of tRNA^Glu gene with and without the m.A14693G and m.A14696G mutations.

Figure 4 Alignment of tRNA^Glu gene from various species, arrows indicated the positions of 51 and 54, corresponding to the m.A14696G and m.A14693G mutations.

Figure 5 Prediction of tRNA^Glu secondary structure with and without the m.A14696G and m.A14693G mutations.

Figure 6 Analysis of mitochondrial functions in cybrids. (A) mtDNA copy number; (B) ATP analysis; (C) ROS analysis; (D) MMP analysis.

Table 3 The Pathogenicity Scoring System for m.A14693G and m.A14696G Mutations

Scoring Criteria	m.A14693G Mutation	Score	m.A14696G Mutation	Score	Classification
More than one independent report	Yes	2	Yes	2	≤6 points: neutral polymorphisms; 7~10 points: possibly pathogenic; ≥11 points (including trans-mitochondrial cybrid studies): definitely pathogenic.
Evolutionary conservation of the base pair	No changes	2	No changes	2
Variant heteroplasmy	No	0	Yes	2
Segregation of the mutation with disease	Yes	2	Yes	2
Histochemical evidence of mitochondrial disease	No evidence	0	No evidence	0
Biochemical defect in complex I, III or IV	No	0	No	0
Evidence of mutation segregation with biochemical defect from single-fiber studies	No	0	No	0
Mutant mt-tRNA steady-state level or evidence of pathogenicity in trans-mitochondrial cybrid studies	Strong evidence	5	Weak evidence	3
Maximum score	Definitely pathogenic	11	Possibly pathogenic	9

Data Sharing Statement

The datasets used and analyzed during the current study are available from corresponding author (Chun Wang, E-mail: [email protected]) on reasonable request.