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Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant
Abhimanyu Garg, … , Anil K. Agarwal, Prashant Mishra
Abhimanyu Garg, … , Anil K. Agarwal, Prashant Mishra
Published October 25, 2022
Citation Information: J Clin Invest. 2022;132(23):e156864. https://doi.org/10.1172/JCI156864.
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Concise Communication Endocrinology Genetics Article has an altmetric score of 42

Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant

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Abstract

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.

Authors

Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, Prashant Mishra

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Figure 1

Growth charts, clinical pictures and pedigree of the patient.

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Growth charts, clinical pictures and pedigree of the patient.
(A) Height...
(A) Height of proband from age 5–19 years, shown as triangles, compared to normal values shown as the third, fiftieth, and ninety-seventh percentiles. (B) Body weight of proband from age 5–19 years, shown as triangles, compared to normal values from the Centers for Disease Control shown as the third, fiftieth, and ninety-seventh percentiles. (C) Anterior view of the proband at 12 years of age, showing proportionate short stature, small mandible, and muscular extremities. (D) Anterior view of the proband’s face, showing recession of scalp hair from the frontal region and small mandible with protruding maxillary central incisors. (E) Lateral view of the proband’s face, showing marked recession of the chin indicative of mandibular hypoplasia. (F) Anterior view of the proband’s mouth, showing crowding of both the maxillary and mandibular teeth. (G) Posterior view of the trunk and gluteal region of the proband showing marked muscularity and loss of subcutaneous fat indicative of lipodystrophy. (H) MAD 5700 pedigree with genotype and phenotype data. Circles denote females, and squares denote males. Symbols filled with black represent affected individuals with the progeroid syndrome, whereas white symbols indicate unaffected individuals. The number in the center of the symbol indicates pedigree number. Slanted arrow indicates the proband. Diagonal line across the symbol indicates deceased individual. The genotypes, age, height, weight, and body mass index (BMI) of the individuals are given under the symbols. Individuals with heterozygous c.86C>T TOMM7 variant are indicated with “C/T,” and the proband with the homozygous variant is indicated with “T/T.”

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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