@article {956, title = {Recurrent homozygous damaging mutation in , encoding a protein disulfide isomerase, in four families with microlissencephaly.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {274-282}, abstract = {

BACKGROUND: Protein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.

METHODS: Eight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.

RESULTS: An identical homozygous variant in (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While is an activator of cellular repeat expansion toxicity, patients showed no evidence of repeat expansions.

CONCLUSION: The c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of expansions. is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Consanguinity, Endoplasmic Reticulum, Exons, Female, Genetic Predisposition to Disease, Homozygote, Humans, Male, Membrane Proteins, Microcephaly, Mutation, Protein Disulfide-Isomerases, Protein Folding, Thioredoxins, Whole Exome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106409}, author = {Ghosh, Shereen Georges and Wang, Lu and Breuss, Martin W and Green, Joshua D and Stanley, Valentina and Yang, Xiaoxu and Ross, Danica and Traynor, Bryan J and Alhashem, Amal M and Azam, Matloob and Selim, Laila and Bastaki, Laila and Elbastawisy, Hanan I and Temtamy, Samia and Zaki, MAH and Gleeson, Joseph G} } @article {179, title = {Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {528-34}, abstract = {

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

}, keywords = {Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3256}, author = {Akizu, Naiara and Cantagrel, Vincent and Zaki, Maha S and Al-Gazali, Lihadh and Wang, Xin and Rosti, Rasim Ozgur and Dikoglu, Esra and Gelot, Antoinette Bernabe and Rosti, Basak and Vaux, Keith K and Scott, Eric M and Silhavy, Jennifer L and Schroth, Jana and Copeland, Brett and Schaffer, Ashleigh E and Gordts, Philip L S M and Esko, Jeffrey D and Buschman, Matthew D and Field, Seth J and Napolitano, Gennaro and Abdel-Salam, Ghada M and Ozgul, R Koksal and Sag{\i}roglu, Mahmut Samil and Azam, Matloob and Ismail, Samira and Aglan, Mona and Selim, Laila and Mahmoud, Iman G and Abdel-Hadi, Sawsan and Badawy, Amera El and Sadek, Abdelrahim A and Mojahedi, Faezeh and Kayserili, H{\"u}lya and Masri, Amira and Bastaki, Laila and Temtamy, Samia and M{\"u}ller, Ulrich and Desguerre, Isabelle and Casanova, Jean-Laurent and Dursun, Ali and G{\"u}nel, Murat and Gabriel, Stacey B and de Lonlay, Pascale and Gleeson, Joseph G} }