Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.
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Rawlins Lettie E, Maroofian Reza, Cannon Stuart J, Daana Muhannad, Zamani Mina, Ghani Shamsul, Leslie Joseph S, Ubeyratna Nishanka, Khan Nasar, Khan Hamid, Scardamaglia Annarita, Cloarec Robin, Khan Shujaat Ali, Umair Muhammad, Sadeghian Saeid, Galehdari Hamid, Al-Maawali Almundher, Al-Kindi Adila, Azizimalamiri Reza, Shariati Gholamreza, Ahmad Faraz, Al-Futaisi Amna, Rodriguez Cruz Pedro M, Salazar-Villacorta Ainara, Ndiaye Moustapha, Diop Amadou G, Sedaghat Alireza, Saberi Alihossein, Hamid Mohammad, Zaki Maha S, Vona Barbara, Owrang Daniel, Alhashem Abdullah M, Obeid Makram, Khan Amjad, Beydoun Ahmad, Najjar Marwan, Tajsharghi Homa, Zifarelli Giovanni, Bauer Peter, Hakami Wejdan S, Al Hashem Amal M, Boustany Rose-Mary N, Burglen Lydie, Alavi Shahryar, Gunning Adam C, Owens Martina, Karimiani Ehsan G, Gleeson Joseph G, Milh Mathieu, Salah Somaya, Khan Jahangir, Haucke Volker, Wright Caroline F, McGavin Lucy, Elpeleg Orly, Shabbir Muhammad I, Houlden Henry, Ebner Michael, Baple Emma L, Crosby Andrew H
Аннотация
METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.
RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.
CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.