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

Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant

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 2

Identification of a Pro29Leu variant in the TOMM7 gene.

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Identification of a Pro29Leu variant in the TOMM7 gene. (A) Schematic of...
(A) Schematic of segments on chromosome 7 of the proband (MAD5700.25) and his parents (MAD5700.12, 13) and sisters (MAD5700.23, 24), based on GRCh37/hg19 coordinates. For each individual, the top line displays markers with homozygous genotypes and the bottom line displays markers with heterozygous genotypes. The homozygous regions inferred from WES data are shown in gray (~1 Mb) and those derived from WGS (~0.8 Mb, chr7:22,506,999-23,366,145) shown with red. The two siblings of the proband and the parents did not share the homozygous region. (B) The location of various genes in the homozygous region on chromosome 7, the gene structure of TOMM7, and the location of the mutation in the proband. Human TOMM7 contains three exons (shown in black rectangles) and two introns (shown as a line). The pathogenic variant c.86C>T in TOMM7 is located in exon 1 (red arrow). (C) Sequence electropherogram for WT (top) sequence in exon 1 of TOMM7, MAD5700.12 (middle) showing heterozygous (het) c.86C>T variant, and MAD5700.25 (bottom) showing the homozygous (hom) c.86C>T variant. (D) An overview of the cryo-electron microscope structure for human TOM complex (PDB ID 7CK6). TOMM7 is shown in red, TOMM5 in gray, TOMM6 in orange, TOMM22 in blue, and TOMM40 in green. The expanded view shows the region surrounding residue proline (Pro) 29 in TOMM7, with nearby amino acids phenylalanine (Phe) 27, isoleucine (Ile) 28, and valine (Val) 31 forming interactions with TOMM40 (green). (E) Protein alignment of TOMM7 from the indicated organisms. Note that Proline 29 (highlighted in yellow) is conserved amongst all the phyla aligned. The three α-helices are indicated by gray bars.