Browsing by Author "Campeau, Philippe M."

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    Juvenile Paget’s Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor Sp7)
    (Elsevier, 2020-08) Whyte, Michael P.; Campeau, Philippe M.; McAlister, William H.; Roodman, G. David; Kurihara, Nori; Nenninger, Angela; Duan, Shenghui; Gottesman, Gary S.; Bijanki, Vinieth N.; Sedighi, Homer; Veis, Deborah J.; Mumm, Steven; Medicine, School of Medicine
    Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z-score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget's disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B, trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD.
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    A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay
    (Nature, 2018) Mucha, Bettina E.; Banka, Siddhart; Ajeawung, Norbert Fonya; Molidperee, Sirinart; Chen, Gary G.; Koenig, Mary Kay; Adejumo, Rhamat B.; Till, Marianne; Harbord, Michael; Perrier, Renee; Lemyre, Emmanuelle; Boucher, Renee-Myriam; Skotko, Brian G.; Waxler, Jessica L.; Thomas, Mary Ann; Hodge, Jennelle C.; Gecz, Jozef; Nicholl, Jillian; McGregor, Lesley; Linden, Tobias; Sisodiya, Sanjay M.; Sanlaville, Damien; Cheung, Sau W.; Ernst, Carl; Campeau, Philippe M.; Medical and Molecular Genetics, School of Medicine
    Purpose Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.
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    The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders
    (Oxford University Press, 2024) Sidpra, Jai; Sudhakar, Sniya; Biswas, Asthik; Massey, Flavia; Turchetti, Valentina; Lau, Tracy; Cook, Edward; Alvi, Javeria Raza; Elbendary, Hasnaa M.; Jewell, Jerry L.; Riva, Antonella; Orsini, Alessandro; Vignoli, Aglaia; Federico, Zara; Rosenblum, Jessica; Schoonjans, An-Sofie; de Wachter, Matthias; Alvarez, Ignacio Delgado; Felipe-Rucián, Ana; Haridy, Nourelhoda A.; Haider, Shahzad; Zaman, Mashaya; Banu, Selina; Anwaar, Najwa; Rahman, Fatima; Maqbool, Shazia; Yadav, Rashmi; Salpietro, Vincenzo; Maroofian, Reza; Patel, Rajan; Radhakrishnan, Rupa; Prabhu, Sanjay P.; Lichtenbelt, Klaske; Stewart, Helen; Murakami, Yoshiko; Löbel, Ulrike; D'Arco, Felice; Wakeling, Emma; Jones, Wendy; Hay, Eleanor; Bhate, Sanjay; Jacques, Thomas S.; Mirsky, David M.; Whitehead, Matthew T.; Zaki, Maha S.; Sultan, Tipu; Striano, Pasquale; Jansen, Anna C.; Lequin, Maarten; de Vries, Linda S.; Severino, Mariasavina; Edmondson, Andrew C.; Menzies, Lara; Campeau, Philippe M.; Houlden, Henry; McTague, Amy; Efthymiou, Stephanie; Mankad, Kshitij; Radiology and Imaging Sciences, School of Medicine
    Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.
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    UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism
    (Cell Press, 2021-01-07) Li, Chunmei; Beauregard-Lacroix, Eliane; Kondratev, Christine; Rousseau, Justine; Heo, Ah Jung; Neas, Katherine; Graham, Brett H.; Rosenfeld, Jill A.; Bacino, Carlos A.; Wagner, Matias; Wenzel, Maren; Al Mutairi, Fuad; Al Deiab, Hamad; Gleeson, Joseph G.; Stanley, Valentina; Zaki, Maha S.; Kwon, Yong Tae; Leroux, Michel R.; Campeau, Philippe M.; Medical and Molecular Genetics, School of Medicine
    The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.