Baple, EL

Crosby, AH

Houlden, H

Zollo, M

English

UCL Discovery

Reply to Karakaya et al.: PRUNE1, a disease-causing gene for secondary microcephaly  Authors:  Emma L Baple1, Henry Houlden2, Massimo Zollo3,4,5, Andrew H Crosby1  1. Medical Research (Level 4), RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK 2. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 3. Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy 4. CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy 5. European School of Molecular Medicine, SEMM, University of Milan, Italy  Correspondence may be addressed to: Dr Emma L. Baple,  Medical Research (Level 4), RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust,  Barrack Road, Exeter, EX2 5DW, UK. E-mail: E.Baple@exeter.ac.uk        In their Letter to the Editor Karakaya et al. present an interesting case report describing the clinical course involving secondary microcephaly of a three year old Turkish boy found to be homozygous for a frameshift mutation in PRUNE1 identified through whole exome sequencing. The child presented with congenital hypotonia, contractures and global developmental delay. Respiratory insufficiency and seizures developed in the first year of life. The authors note that the affected child's head circumference plotted on the 75th centile at birth, and that by 38 months of age he had developed microcephaly.  Neuroimaging at 14 months revealed cerebral and cerebellar atrophy consistent with other patients described with Prune syndrome (Karaca et al., 2015; Zollo et al., 2017; Costain et al., 2017).  Although the child had abnormal neurology from birth, there was a period of early developmental regression. Peripheral spasticity in the lower extremities and optic atrophy were not documented until 38 months. In addition to the PRUNE1 variant Karakaya et al also identified a second homozygous variant in the CCDC14 gene in the Turkish child’s whole exome sequencing data which, while listed to have an allele count of 108 in the current Genome Aggregation Database (gnomAD) release, is notably absent in homozygous fashion (Lek et al., 2016). CCDC14 is known to be expressed in human brain, reported to negatively regulate centriole duplication and interact with proteins previously associated with primary microcephaly (Firat-Karalar et al.,2014). Thus, while it seems likely that the homozygous PRUNE1 variant is primarily responsible for the clinical presentation in the Turkish child, it is impossible to determine whether there may be any phenotypic contribution from this additional homozygous sequence variant.   Recently, Costain et al. described a homozygous consensus splice site variant in PRUNE1 (c.521-2A>G; NM_021222.1) in a two year old Oji-Cre male who presented with congenital hypotonia and talipes, whose head circumference was large at birth at birth (+3 standard deviations), but by two years and 2 months plotted on the 50th centile, with a weight and height on the 95th and 75th centiles respectively.  However, it should be noted that the child’s father is macrocephalic (+4 standard deviations), the published clinical photographs at 2 years 5 months of age illustrate bitemporal narrowing, a slopping forehead and large ears consistent with a developing microcephaly and neuroimaging revealed cortical and cerebellar atrophy. He developed respiratory insufficiency shortly after birth, and infantile spasms in the first year of life (Costain et al., 2017).  As more cases are published the phenotype associated with the autosomal recessive Prune neurodevelopmental disorder is becoming clearer. It is now apparent that while some patients have a small head at birth and others a head circumference in the normal range, the key component of the microcephaly is that it is progressive, and associated with characteristic neuroimaging findings with a thin or hypoplastic corpus callosum and cortical and cerebellar atrophy developing in early childhood.  Although all patients with Prune syndrome described to date are neurologically impaired from birth, there also appears to be a neurodegenerative component with progression of the disorder. In our manuscript, we described clinical overlap of Prune syndrome with the neurodegenerative condition associated with homozygous mutations in TBCD (Zollo et al., 2017). TBCD encodes one of the five tubulin-specific chaperones that are required for α/β-tubulin de novo heterodimer formation and the disorder is characterized by developmental regression, seizures, optic atrophy and secondary microcephaly, cortical atrophy with delayed myelination, cerebellar atrophy and thinned corpus callosum (Edvardson et al., 2016; Flex et al., 2016; Miyake et al., 2016; Pode-Shakked et al., 2016.  The neurodegenerative phenotype documented in the Turkish child by Karakaya et al. further demonstrates the similarities with the TBCD disorder, and Prune syndrome and confirms optic atrophy to be a feature of Prune syndrome. Interestingly, it is also becoming clear that respiratory insufficiency is a common feature of Prune syndrome having been documented by Karakaya et al. and in the Oji-Cre child, as well as the youngest affected Omani child described in our manuscript.   Web Sources The URLs for data presented herein are as follows: Genome Aggregation Database (gnomAD); http://gnomad.broadinstitute.org  References Costain G, Shugar A, Krishnan P, Mahmutoglu S, Laughlin S, Kannu P. Homozygous mutation in PRUNE1 in an Oji-Cree male with a complex neurological phenotype. Am J Med Genet A 2017; 173(3): 740-3.  Edvardson S, Tian G, Cullen H, Vanyai H, Ngo L, Bhat S et al. Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway. Hum Mol Genet 2016Aug 29. pii: ddw292. PMID: 27571896 DOI: 10.1093/hmg/ddw29.  Firat-Karalar EN, Rauniyar N, Yates JR 3rd, Stearns T. Proximity Interactions among Centrosome Components Identify Regulators of Centriole Duplication. Curr Biol. 2014 Mar 17;24(6):664-70.  Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A et al. Biallelic mutations in TBCD, encoding the tubulin folding cofactor D, perturb microtubule dynamics and cause early-onset encephalopathy. Am J Hum Genet 2016; 99: 962–73.  Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z, et al. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron 2015; 88(3): 499-513.  Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536: 285–91.  Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H et al. Biallelic TBCD mutations cause early-onset neurodegenerative encephalopathy. Am J Hum Genet 2016; 99: 950–61.  Pode-Shakked B, Barash H, Ziv L, Gripp KW, Flex E, Barel O et al. Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy. Clin Genet 2016 Nov 2. doi: 10.1111/cge.12914. PMID: 27807845 DOI: 10.1111/cge.12914.  Zollo M, Ahmed M, Ferrucci V, Salpietro V, Asadzadeh F, Carotenuto M, et al. PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. Brain 2017; 140(4): 940-52.   

Reply: PRUNE1: a disease-causing gene for secondary microcephaly

https://discovery.ucl.ac.uk/id/eprint/10087804/3/Houlden%20Reply%20to%20Karakaya%20et%20al%20PRUNE1%2C%20a%20disease-causing%20gene%20for%20secondary%20microcephaly%20.pdf

Reply: PRUNE1: a disease-causing gene for secondary microcephaly

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