LADD syndrome is caused byFGF10mutations

Abstract

Lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] is an autosomal-dominant multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies. Loss of function mutations in FGF10 were recently described in aplasia of the lacrimal and salivary glands [ALSG (MIM 180920; MIM 103420)] (Entesarian et al., Nat Genet 2005: 37: 125-127, Milunsky et al., American College of Medical Genetics Annual Meeting, Dallas, TX, 2005: A100). Due to the significant phenotypic overlap between LADD syndrome and ALSG and the variable expressivity of both the disorders, we hypothesized that FGF10 mutations could also result in LADD syndrome. A de novo missense mutation was found in exon 3 of FGF10 in a 3-year-old female (Family 1) with LADD syndrome. This missense mutation, resulting in a non-conservative amino acid change, was confirmed by restriction enzyme digestion and was not found in 500 control chromosomes. A nonsense mutation was also found in exon 2 of FGF10 (Family 2) in a 19-year-old mother with ALSG and her 2-year-old daughter with LADD syndrome. Previous studies of FGF10 mutant mice have demonstrated abnormalities consistent with ALSG and LADD syndrome. We conclude that ALSG and LADD syndrome may represent variable presentations of the same clinical spectrum caused by FGF10 mutations.

FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)

“…It has been hypothesized that ALSG results from haploinsufficiency of FGF10 whereas LADD syndrome is caused by a more complex mechanism involving residual activity derived from the mutant allele. However, this is contradicted by the finding by Milunsky et al 5 of a nonsense mutation in FGF10 in a mother with ALSG and her daughter with LADD syndrome. This variability in clinical expression is more likely to be explained by modifier gene loci such as FGFR2 and FGFR3 or, stochastic events.…”

“…1 Two missense mutations have previously been reported in FGF10 and in both cases associated with LADD syndrome. 4,5 In this study, we report for the first time a FGF10 missense mutation associated with isolated ALSG. In family 1, a father and his son are affected by ALSG and they both carry an R80S substitution in FGF10.…”

“…1,4,5 To date, ALSG has exclusively been associated with loss of function mutations in FGF10. This suggests that haploinsufficiency during a critical stage of FGF10 mutations in aplasia of lacrimal and salivary glands M Entesarian et al development causes ALSG.…”

“…1 More recent studies have shown ALSG to be allelic to lacrimo-auriculo-dento-digital (LADD; OMIM 149730) syndrome, which is a similar clinical entity. 4,5 LADD syndrome is an autosomal dominant disorder characterized by aplasia or hypoplasia of the lacrimal and salivary systems as well as abnormalities of the face, ears, eyes, mouth, teeth, digits and genitourinary system. Moreover, LADD syndrome is genetically heterogeneous and may also be caused by mutations in the fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3).…”

Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function

“…Interestingly, a significant number of LADD syndrome patients suffer from hearing defects [1]. In the adult brain (hypothalamus), expression of vivo [38] and we showed that FGF10 can translocate into the nucleus of these cells in vitro (Fig.…”