Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia

Abstract

Background Mutations in ARL6IP1 , which encodes a tetraspan membrane protein localized to the endoplasmic reticulum (ER), have been recently described in a large family with a complicated form of hereditary spastic paraplegia (HSP). Case presentation We sought to expand the HSP phenotype associated with ARL6IP1 variants by examining a Saudi kindred with a clinically more severe presentation, which resulted in spontaneous neonatal death of both affected siblings. Clinical features encompassed not only spastic paraplegia but also developmental delay, microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures, spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and respiratory distress. We performed clinical assessment and radiological studies of this family, in addition to homozygosity mapping and whole exome sequencing (WES) to identify the disease-associated variant. Homozygosity mapping localized the causative gene to a region on chromosome 16 harboring ARL6IP1 . WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein. Allelic expression analysis of the parents demonstrated downward pressure on the mutant allele, suggestive of nonsense-mediated decay. Conclusions Our report shows that the phenotype associated with ARL6IP1 variants may be broader and more acute than so far reported and identifies fatal HSP as the severe end of the phenotypic spectrum of ARL6IP1 variants.

Defective lysosome reformation during autophagy causes skeletal muscle disease

“…Mechanistic understanding of the processes responsible for regulating ALR, as we revealed here for INPP5K-related muscular dystrophy, may reveal unrecognized disease genes and disorders associated with defects in this pathway. Interestingly, INPP5K binds the protein ARL6IP1 ( 72 ), mutations in which occur in hereditary spastic paraplegia ( 98 , 99 ). Additionally, recent proteomics analysis of purified autolysosome membranes has identified additional proteins with functional links to PI( 4 )P/PI(4,5)P 2 and associations with human disease, but with as yet undefined roles in ALR ( 30 ).…”

“…The majority of INPP5K disease mutations are located within the catalytic 5-phosphatase domain, exhibit decreased hydrolysis of PI(4,5)P2 (37,38) and as shown here were unable to restore ALR in myoblasts with loss of INPP5K function. Muscular dystrophy directly caused by a primary defect in lysosome function (17,77,78), or primary defects in the autophagy pathway (7 (98,99). Additionally, recent proteomics analysis of purified autolysosome membranes has identified additional proteins with functional links to PI(4)P/PI(4,5)P2, and associations with human disease, but with as yet undefined roles in ALR (30).…”

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

“…For example, the small GTPases Rab10 and Rab18 regulate tubular ER morphology: depletion of Rab10 produces expansion of cisternal ER and fewer ER tubules (English and Voeltz, 2013), and loss of Rab18 from ER tubules, by depletion of the Rab3GAP complex (which is also a Rab18 GEF), causes fragmentation of the ER tubular network and spread of ER sheets (Gerondopoulos et al, 2014). Another example is the RNA-binding protein Ataxin-2, also associated (Fowler and O'Sullivan, 2016) HSP (Novarino et al, 2014;Wakil et al, 2019) Ataxin-2 Tubular ER morphogenesis KD: short and bulged neurites (del Castillo et al, 2019) ALS (Elden et al, 2010) SCA (Pulst et al, 1996) ATL1 Tubular ER morphogenesis LDs growth regulation KD: Reduced axon growth (Zhu et al, 2006) *KD: Decreased spontaneous release; impaired anterograde transport (De Gregorio et al, 2017); impaired regeneration (Levitan et al, 2016;Rao et al, 2016) *LOF: Fragmented presynaptic ER; Decreased evoked transmitter release (Summerville et al, 2016); increased number of presynaptic terminals (Lee et al, 2009) *OE: Decreased spontaneous release; reduced anterograde transport (De Gregorio et al, 2017); Decreased evoked transmitter release (Summerville et al, 2016) HSN (Guelly et al, 2011) HSP (Zhao et al, 2001) ATL3 Tubular ER morphogenesis Autophagy-mediated tubular ER turnover LOF: Decreased mitochondrial number (Krols et al, 2019) LOF: Impaired neurite outgrowth (Behrendt et al, 2019) *KD: Decreased spontaneous release; reduced anterograde transport (De Gregorio et al, 2017); impaired regeneration (Levitan et al, 2016;Rao et al, 2016) *LOF: Fragmented presynaptic ER; Decreased evoked transmitter release (Summerville et al, 2016); increased number of presynaptic terminals (Lee et al, 2009) *OE: Decreased spontaneous release; reduced anterograde transport (De Gregorio et al, 2017); Decreased evoked transmitter release (Summerville et al, 2016) HSN (Fischer et al, 2014;<...>…”

In vivo Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale

“…LYS: lysosomes. For the disease genes and diseases depicted here, besides the literature cited in the text, refer to Novarino et al (2014); Wakil et al (2019) (ARF-like 6 interacting protein 1 mutations in neuropathy with spastic paraplegia, microcephaly, leukoencephalopathy, and seizures); Griscelli and Prunieras (1978) (mutations in RAB2 in Griscelli syndrome affecting the immune system); Cogli et al (2009); Lupo et al (2009); Stendel et al (2010), for the motor and sensory neuropathies Charcot-Marie-Tooth type 2B and type 4 (CMT2B and CMT4), caused by mutations in RAB7 and RAB11 effector SH3TC2, respectively; Harvey et al (2010) (mutations in the ARF-specific GAP encoding gene AGAP1 in pediatric high-risk B-cell ALL); Roberti et al (2009) (gene rearrangement in the RAB-specific GAP encoding gene RABGAP1L in patient with Klinefelter syndrome who developed AML).…”