Alternative titles; symbols
HGNC Approved Gene Symbol: PEX16
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:45,909,663-45,918,822 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Peroxisome biogenesis disorder 8A (Zellweger) | 614876 | Autosomal recessive | 3 |
| Peroxisome biogenesis disorder 8B | 614877 | Autosomal recessive | 3 |
Honsho et al. (1998) isolated a human PEX16 cDNA by performing an expressed sequence tag (EST) homology search on a human DNA database and by using yeast PEX16 from Yarrowia lipolytica to screen a human liver cDNA library. This cDNA was found to encode a peroxisomal protein, peroxin 16, that contains 336 amino acids. Among 13 peroxisome-deficiency complementation groups, PEX16 expression morphologically and biochemically restored peroxisome biogenesis only in fibroblasts from a case of Zellweger syndrome of the complementation group referred to as CGD in Japan and CG9 in the United States. PEX16 was localized to peroxisomes through expression study of epitope-labeled PEX16 protein.
South and Gould (1999) characterized wildtype PEX16 and found that it has an apparent molecular mass of about 38 kD by SDS/PAGE. Sequence analysis revealed 2 transmembrane domains, 1 spanning amino acids 110-144 and another spanning amino acids 222-243. Protease protection experiments revealed a membrane orientation where the N- and C-termini extend into the cytoplasm and the intermembrane loop is protected within the peroxisome lumen.
South and Gould (1999) found that fibroblasts from the patient carrying the R176X mutation (603360.0001) were unable to import PMP70 (170995) into peroxisomes. Transfection and overexpression of wildtype PEX16 did not induce peroxisome proliferation, but restored PMP70 import. The authors concluded that PEX16-mediated formation of peroxisomes does not require the division of preexisting peroxisomes. By characterizing various truncation mutants, Honsho et al. (2002) determined that a positively charged region (amino acids 66-81) and the first transmembrane domain are required for peroxisome targeting of PEX16. The C-terminal cytoplasmically exposed region of PEX16 functioned in peroxisome formation. Transfection and overexpression of the R176X mutation interfered with membrane protein transport.
Sugiura et al. (2017) followed the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes and showed that the essential import receptors Pex3 (603164) and Pex14 (601791) target mitochondria, where they are selectively released into vesicular pre-peroxisomal structures. Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion with endoplasmic reticulum-derived vesicles carrying Pex16, thereby providing full import competence. Sugiura et al. (2017) concluded that their findings demonstrated the hybrid nature of newly born peroxisomes, expanding their functional links to mitochondria.
In the study by Honsho et al. (1998), one patient with a peroxisomal biogenesis disorder was found to have a homozygous nonsense mutation (603360.0001) in the PEX16 gene.
In 6 patients, including 2 sibs, with a relatively mild form of Zellweger syndrome characterized by early-childhood onset of progressive spastic paraparesis and ataxia with progressive leukodystrophy and brain atrophy on brain MRI, Ebberink et al. (2010) identified 5 different homozygous mutations in the PEX16 gene (see, e.g., 603360.0003-603360.0005). Studies of skin fibroblasts showed that peroxisomes were markedly enlarged in size and reduced in number compared to controls. However, biochemical studies showed only mild abnormalities, such as increased very-long-chain fatty acids, and increased bile acid intermediates or increased branched chain fatty acids in some. Phytanic acid alpha-oxidation, pristanic acid beta-oxidation, and red cell plasmalogen were normal. Peroxisomal enzymes were normal, and the peroxisomes were import-competent. Expression of wildtype PEX16 restored the number and size of peroxisomes in patient fibroblasts to normal. Expression of mutant PEX16 in PEX16-null cells resulted in enlarged peroxisomes in about 30% of cells, indicating some residual activity. Ebberink et al. (2010) emphasized that even though PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with a relatively mild phenotype showing import-competent peroxisomes in fibroblasts.
In fibroblasts from a patient with Zellweger syndrome of complementation group D (PBD8A; 614876), purchased from the NIGMS Human Genetic Mutant Cell Repository (GM06231), Honsho et al. (1998) demonstrated deficiency of peroxin-16 and a nonsense mutation in the PEX16 gene: a C-to-T transition at nucleotide 526, resulting in a change of codon 176 from CGA (arg) to TGA (stop).
Shimozawa et al. (2002) identified a homozygous splice site mutation (IVS10+2T-C) in 2 complementation group D patients (PBD8A; 614876), causing exon 10 deletion and changing the amino acid sequence starting from codon 298, introducing a termination codon at position 336.
In 2 sibs, born of consanguineous Turkish parents, with a peroxisomal biogenesis disorder (PBD8B; 614877), Ebberink et al. (2010) identified a homozygous 1-bp deletion (984delG) in exon 11a of the PEX16 gene, resulting in a frameshift and premature protein truncation. Exon 11b was unaffected. Both patients presented between age 1 and 2 years with delayed walking and frequent falls after normal initial development. The disorder was progressive, characterized by lower limb spasticity and ataxia resulting in wheelchair-dependence in the first decade. Studies of skin fibroblasts showed that peroxisomes were markedly enlarged in size and reduced in number compared to controls. However, biochemical studies showed only mild abnormalities, such as increased very-long-chain fatty acids (VLCFA), increased bile acid intermediates, and increased branched chain fatty acids (only found in 1 sib). Expression of wildtype PEX16 restored the number and size of peroxisomes in patient fibroblasts to normal. Ebberink et al. (2010) emphasized that even though PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with a relatively mild phenotype showing import-competent peroxisomes in fibroblasts.
In a girl with a relatively mild type of peroxisomal biogenesis disorder (PBD8B; 614877), Ebberink et al. (2010) identified a homozygous 992A-G transition in exon 11a of the PEX16 gene, resulting in a tyr331-to-cys (Y331C) substitution. She developed an ataxic gait at age 2 years, after normal initial development except for delayed walking. At age 6 years, she had mild cognitive impairment, moderate dysarthria, and abnormal eye saccades. Brain MRI showed widespread white matter changes on a background pattern of global delay in myelin maturation, and reduced cerebellar volume. Similar MRI findings were observed in her younger sister. Studies of skin fibroblasts showed that peroxisomes were markedly enlarged in size and reduced in number compared to controls. However, biochemical studies showed only mild abnormalities, such as increased VLCFA, but most other peroxisomal functions appeared normal.
In an Indian girl, born of consanguineous parents, with a relatively mild type of peroxisomal biogenesis disorder (PBD8B; 614877), Ebberink et al. (2010) identified a homozygous large intragenic deletion of intron 10 and exon 11 of the PEX16 gene. In transcript variant 1, the deletion affected the last 468 base pairs of intron 10, the entire exon 11a, and the first 80 base pairs of the 3-prime flanking region of exon 11a. In transcript variant 2, the deletion affected the last 603 base pairs of intron 10, and the first 4 base pairs of exon 11b. The deletion resulted in 3 alternative splice products. She showed normal development for the first year of life, but then stopped acquiring new skills, and lost her ability to walk independently at age 24 months due to spasticity and mild ataxia. Her speech and other cognitive functions also deteriorated slowly over time. At the age of 5 years, she had nystagmus, cataracts, hyperreflexia, clonus, and extensor plantar responses. Brain imaging showed diffuse white matter abnormalities and focal atrophy of the cerebellum and corpus callosum. Peripheral nerve velocity studies of the lower limbs suggested demyelination. Studies of skin fibroblasts showed that the peroxisomes were markedly enlarged in size and reduced in number compared to controls. However, biochemical studies showed only mild abnormalities, such as increased VLCFA, but most other peroxisomal functions appeared normal.
Ebberink, M. S., Csanyi, B., Chong, W. K., Denis, S., Sharp, P., Mooijer, P. A. W., Dekker, C. J. M., Spooner, C., Ngu, L. H., De Sousa, C., Wanders, R. J. A., Fietz, M. J., Clayton, P. T., Waterham, H. R., Ferdinandusse, S. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J. Med. Genet. 47: 608-615, 2010. [PubMed: 20647552] [Full Text: https://doi.org/10.1136/jmg.2009.074302]
Honsho, M., Hiroshige, T., Fujiki, Y. The membrane biogenesis peroxin Pex16p: topogenesis and functional roles in peroxisomal membrane assembly. J. Biol. Chem. 277: 44513-44524, 2002. [PubMed: 12223482] [Full Text: https://doi.org/10.1074/jbc.M206139200]
Honsho, M., Tamura, S., Shimozawa, N., Suzuki, Y., Kondo, N., Fujiki, Y. Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D. Am. J. Hum. Genet. 63: 1622-1630, 1998. [PubMed: 9837814] [Full Text: https://doi.org/10.1086/302161]
Shimozawa, N., Nagase, T., Takemoto, Y., Suzuki, Y., Fujiki, Y., Wanders, R. J. A., Kondo, N. A novel aberrant splicing mutation of the PEX16 gene in two patients with Zellweger syndrome. Biochem. Biophys. Res. Commun. 292: 109-112, 2002. [PubMed: 11890679] [Full Text: https://doi.org/10.1006/bbrc.2002.6642]
South, S. T., Gould, S. J. Peroxisome synthesis in the absence of preexisting peroxisomes. J. Cell. Biol. 144: 255-266, 1999. [PubMed: 9922452] [Full Text: https://doi.org/10.1083/jcb.144.2.255]
Sugiura, A., Mattie, S., Prudent, J., McBride, H. M. Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes. Nature 542: 251-254, 2017. [PubMed: 28146471] [Full Text: https://doi.org/10.1038/nature21375]