RESUMEN
Hereditary sensory and autonomic neuropathies (HSAN) type II are characterized by autosomal recessive inheritance, onset at birth and self-mutilating behavior. Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia. Whole-exome sequencing showed a homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37) in ARL6IP1. The protein harbors reticulon-like short hairpin transmembrane domains and has a role in endoplasmic reticulum shaping. The variant causes an additional C-terminus hydrophobic domain which could disrupt its function. ARL6IP1 interacts with atlastin-1 responsible for SPG3A and HSAN type ID. This report highlights the role of ARL6IP1 in the pathophysiology of insensitivity to pain and spastic paraplegia.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Predisposición Genética a la Enfermedad/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Proteínas de la Membrana/genética , Mutación , Insensibilidad Congénita al Dolor/genética , Paraplejía/genética , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , Femenino , Homocigoto , Humanos , Masculino , Linaje , Secuenciación del Exoma/métodosRESUMEN
Pre-axial polydactyly type II (PPDII, MIM #174500), Werner mesomelic syndrome (MIM %188770) and Haas polysyndactyly (MIM #186200) are a group of closely related conditions caused by mutations in a long-range Sonic hedgehog (SHH, MIM *600725) regulator called ZRS. To date, 19 point mutations, 10 duplications and 1 triplication of the ZRS associated with those pre-axial polydactylies have been reported in humans, mice, cats and chickens. Some of these have been shown to cause ectopic expression of Shh in the limb bud in mice, leading to a polydactylous phenotype, but the precise mechanism by which ZRS mutations generate this phenotype remains unknown. We present two PPDII families with fully penetrant point mutations in ultra-conserved predicted binding sites for transcription factors SOX9 and PAX3, two possible candidates for regulating SHH expression. Screening for point mutations or copy-number variation of the ZRS, high-resolution array-CGH, and screening of other conserved non-coding sequences (CNS) surrounding SHH in a third family are negative. This is the sixth PPDII pedigree with possible linkage to 7q36 that presents with no detectable ZRS mutation. We hypothesize that another nearby regulatory sequence, or an undetected position effect between ZRS and SHH, could be responsible for negative familial cases linked to 7q36.