A cluster of metabolic defects caused by mutation in a mitochondrial tRNA

Abstract

Hypertension and dyslipidemia are risk factors for atherosclerosis and occur together more often than expected by chance. Although this clustering suggests shared causation, unifying factors remain unknown. We describe a large kindred with a syndrome including hypertension, hypercholesterolemia, and hypomagnesemia. Each phenotype is transmitted on the maternal lineage with a pattern indicating mitochondrial inheritance. Analysis of the mitochondrial genome of the maternal lineage identified a homoplasmic mutation substituting cytidine for uridine immediately 5' to the mitochondrial transfer RNA(Ile) anticodon. Uridine at this position is nearly invariate among transfer RNAs because of its role in stabilizing the anticodon loop. Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.

Fig. 1

The structure of Kindred 129. Individuals with serum Mg²⁺ < 1.8 mg/dl are indicated by black symbols. Family members taking antihypertensive medications or having blood pressures over 140/90 mm Hg are indicated by an H. Members with hypercholesterolemia (serum cholesterol > 200 mg/dl or taking lipid-lowering agents) are denoted by C. Blood relatives who did not have electrolyte values measured are indicated by gray symbols. The index case is indicated by an arrow.

Fig. 2

Renal hypomagnesemia, hypocalciuria, and hypokalemia in the maternal lineage of K129. (A) Serum Mg²⁺ values for individuals in maternal and nonmaternal lineages of K129 are shown and are significantly different (P = 2 × 10⁻⁹). (B) Fractional renal Mg²⁺ excretion (FEMg²⁺) on the maternal and nonmaternal lineages is shown; on the maternal lineage, individuals with normal and low Mg²⁺ levels are separated. Hypomagnesemic subjects have significantly elevated fractional excretion of Mg²⁺, indicating a renal defect (P = 0.0001 comparing maternal to nonmaternal; P = 5 × 10⁻⁶ comparing hypomagnesemic subjects versus those not in the maternal lineage). (C) Urinary calcium to creatinine ratios (UCa/cr) are shown grouped as in (B); maternal subjects have significantly reduced urinary calcium levels (P = 0.0005). (D) Serum K⁺ levels. Hypokalemia is seen predominantly on the maternal lineage among hypomagnesemic subjects.

Fig. 3

Quantitative blood pressure and cholesterol values in K129. Values in maternal and nonmaternal K129 members between the ages of 18 and 60 are shown. All values represent difference from the mean value after adjustment for age, sex, and BMI. For blood pressure and lipids, units are mm Hg and mg/dl, respectively. Mean and SEM values are indicated for maternal and nonmaternal groups. Values are significantly elevated in members of the maternal lineage. (A) Systolic blood pressure (P = 0.00007). (B) Diastolic blood pressure (P = 0.002). (C) Fasting total cholesterol (P = 0.002). (D) Fasting LDL + VLDL cholesterol (P = 0.004).

Fig. 4

Mitochondrial tRNA^Ile mutation in K129. Mitochondrial DNA from both blood leukocytes and renal epithelial cells was analyzed and yielded identical results. (A) A fragment of mtDNA containing the tRNA^Ile gene was amplified from members of K129 and normal controls and was fractionated by nondenaturing gel electrophoresis (18). A thymidine-to-cytidine variant (indicated by arrow) is present in individuals from the maternal lineage (M) but absent in offspring of affected males (paternal lineage, P) and unrelated controls. (B) The sequence of a portion of the mitochondrial tRNA^Ile gene from the amplicon in (A) from a wild-type control (left) and a member of the maternal lineage of K129 (right). A single base substitution (asterisk) changes the wild-type thymidine to cytidine. (C) The T → C transition alters the nucleotide immediately 5′ to the tRNA^Ile anticodon.