Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay

Abstract

Ca 2þ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca 2þ store, and dysregulation of ER Ca 2þ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca 2þ-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca 2þ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca 2þ storage, impaired Ca 2þ signaling mediated by the IP 3 R Ca 2þ release channel, and reduced ER Ca 2þ refilling via store-operated Ca 2þ entry. These results, together with the previously described role of CCDC47 in Ca 2þ signaling and development, suggest that bi-allelic loss-offunction variants in CCDC47 underlie the pathogenesis of this multisystem disorder. Ca 2þ signaling is a multipurpose intracellular signaling system that regulates a number of cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, transcription, and cellular proliferation. 1 The endoplasmic reticulum (ER), or the sarcoplasmic reticulum (SR) in muscle cells, is the largest store of intracellular Ca 2þ. 2 ER Ca 2þ depletion is also observed in a number of genetic disorders due to variants in Ca 2þ channels and sensors. For example, Brody myopathy (MIM: 601003) is caused by recessive variants in ATP2A1 (MIM: 611974), which encodes the fast-twitch skeletal muscle sarcoplasmic reticulum Ca 2þ ATPase (SERCA1), 3 while Darier disease (MIM: 124200) occurs due to variants in ATP2A2 (MIM: 108740), which encodes another sarcoplasmic reticulum Ca 2þ ATPase, SERCA2. 4 Minicore myopathy (MIM: 255320) and central core disease (MIM: 117000) result from variants in RYR1 (MIM: 180901), which encodes a major Ca 2þ release channel, 5 and autosomal centronuclear myopathy (MIM: 160150) is associated with variants in MTMR14 (MIM: 611089), which encodes a muscle-specific inositol phosphatase. 6 Stormorken syndrome (MIM: 185070), tubular aggregate myopathy 1 (MIM: 160565), and immunodeficiency 10 (MIM: 612783) are caused by variants in STIM1 (MIM: 605921), 7-9 which encodes a Ca 2þ sensor. Tubular aggregate myopathy 2 (MIM: 615883) and immunodeficiency 9 (MIM: 612782) are caused by variants in ORAI1 (MIM: 610277), 10,11 which encodes a Ca 2þ channel that...

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide

“…2 ). The rarity of the variants identified and the total genome-wide AOH, calculated from WES data, for the Turkish probands is consistent with a clan genomics IBD and transmission genetics homozygosity of a recent mutation in the family or clan versus an older founder allele homozygosed [ 24 ] by geographic or population isolation [ 25 , 26 ] (Fig. 1f ).…”

“…Steel syndrome and associated COL27opathies due to function altering variants in the gene COL27A1 demonstrate how rare recessive variants can come together and account for disease burden in specific populations by autozygosity either through genetic drift of founder alleles in culturally [ 25 , 26 ] or geographically isolated populations such as in Puerto Rico, or consistent with the Clan Genomics hypothesis [ 12 ], through rapid intergenerational IBD homozygosity due to increased consanguinity of parents or “clan members” of affected probands. In addition, the observation that some of these rare variants can contribute in heterozygosity [ 36 ] or in combination with common polymorphisms [ 38 ] to more common complex disorders or to late-onset related clinical presentations [ 37 ] due to life-long exposures in individuals with a sensitized genetic background, gene–environment interactions, further supports the importance of recent rare variation arising in the “clan” as an important contributor to disease susceptibility, versus common variation across multiple populations, and the continuum that connects rare and common diseases.…”

An ER translocon for multi-pass membrane protein biogenesis

“…CCDC47, Nicalin, TMEM147 and NOMO are abundant ER-localized proteins, conserved across eukaryotes, widely expressed in human tissues, and associated with several human diseases ( Itzhak et al, 2016 ; Burdon et al, 2011 ; Sharma et al, 2012 ; Xin et al, 2010 ; Caglayan et al, 2013 ; Alanay et al, 2014 ; Li et al, 2019 ; Reuter et al, 2017 ; Morimoto et al, 2018 ). Although their functions remain obscure, CCDC47 has been linked to various membrane-associated processes ( Morimoto et al, 2018 ; Zhang et al, 2007 ; Konno et al, 2012 ; Thapa et al, 2018 ; Yamamoto et al, 2014 ), and the Nicalin-TMEM147-NOMO complex has been proposed to regulate subunit assembly and localization of several cell surface receptors and ion channels ( Almedom et al, 2009 ; Gottschalk et al, 2005 ; Kamat et al, 2014 ; Rosemond et al, 2011 ). More recently, all four genes were identified in a genome-wide screen for factors that impair surface expression of a mutant TRP channel ( Talbot et al, 2019 ).…”

“…Notably, the long C-terminal coiled-coil of CCDC47 extends to the nascent chain at the ribosome exit tunnel ( Figure 3A,B ). Truncating this conserved motif causes a developmental disorder in humans ( Morimoto et al, 2018 ), suggesting that this interaction is functionally important.…”

“…A general role for the TMCO1 translocon in multi-pass membrane protein biogenesis is consistent with the wide expression and conservation of its subunits, and the numerous cellular and organismal phenotypes associated with their dysfunction. In humans, TMCO1 has been linked to glaucoma ( Burdon et al, 2011 ; Sharma et al, 2012 ), and loss of either TMCO1 ( Xin et al, 2010 ; Caglayan et al, 2013 ; Alanay et al, 2014 ) or CCDC47 ( Morimoto et al, 2018 ) causes rare autosomal recessive developmental disorders. Similarly, a mutation in TMEM147 has been linked to a rare neurodevelopmental disorder manifesting with severe intellectual disability and impaired vision ( Reuter et al, 2017 ).…”