Crisponi Syndrome Is Caused by Mutations in the CRLF1 Gene and Is Allelic to Cold-Induced Sweating Syndrome Type 1

Abstract

Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal, paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stuve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)-receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations. We suggest that the syndromes can comprise a family of "CNTF-receptor-related disorders," of which Crisponi syndrome would be the newest member and allelic to CISS1.

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

“…Consistent with this possibility, ancestors of both parents originate from a small geographic region in Northern India and belong to the same caste. We therefore introduced a consanguineous loop into the family, an approach successfully used in previous positional cloning projects in which consanguinity was only inferred (27), and performed genome-wide linkage analysis assuming recessive inheritance of a homozygous mutation. This revealed four regions with the maximum possible logarithm of odds score of 2.53 (Fig.…”

Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

“…1 Further patients have been reported later. [2][3][4][5][6][7][8] The syndrome usually manifests at birth, when patients present with hyperthermia and abnormal paroxysmal contractions of the facial and oropharyngeal muscles, as well as feeding and respiratory difficulties often requiring the use of nasogastric feeding. Physical dysmorphisms such as a large face, broad nose and camptodactyly have been described in most of the patients.…”

“…Physical dysmorphisms such as a large face, broad nose and camptodactyly have been described in most of the patients. [3][4][5]7,8 Hyperthermia is frequently associated with death within the first months of life. Feeding difficulties and hyperthermia often resolve after infancy in the rare surviving patients, who then develop scoliosis and sometimes psychomotor retardation.…”

“…In pre-adolescent patients, evidence of cold-induced sweating was reported. 3 Cold-induced sweating syndrome type 1 (CISS1) was first reported in two Israeli sisters in 1978. 9 It involves paradoxical sweating at cold ambient temperatures on the upper part of the body, along with progressive scoliosis.…”

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

“…Findings in humans likewise underscore the functional coherence of the three subunits. Thus, human mutations (homozygote or compound) causing dysfunction of CLC:CLF-1 or CNTFRα, all result in the socalled cold-induced sweating/Crisponi syndrome, a condition characterized by symptoms such as impaired suckling and swallowing, various dysmorphic features, temperature spikes, and paradoxical and perfuse sweating at low temperatures [9][10][11] .…”