Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin

Abstract

Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.

Figure 1

Pedigree of family 16. (A key to phenotypes is given in the circle. CHL = conductive hearing loss; ROM = range of motion.) The arrow (↗) denotes the proband. Square symbols denote male patients, and circles denote female patients; blackened symbols denote affected individuals, and unblackened symbols denote unaffected individuals; each quadrant defines a phenotypic element or a set of phenotypic elements, and blackened quadrants indicate the presence of the corresponding phenotypic element(s). Asterisks (*) indicate family members who underwent complete genetic, otolaryngological, ophthalmologic, and radiological evaluations. Horizontal bars (—) indicate family members who were personally examined by an investigator (D.J.B.).

Figure 2

Sequence chromatograms. A, Chromatogram from sequencing of forward strand, demonstrating NOG mutations in affected members of family 16 (top) versus control samples (bottom). The asterisk (*) denotes overlapping peaks—indicating heterozygous mutation c.328C→T (Q110X), not present in control samples. B, Chromatogram from sequencing of forward strand in affected member of family G (top)—demonstrating heterozygous mutation c.252-253insC—as compared to control samples (bottom). Text between chromatograms indicate the sequence of the mutant strand (line 1) and the sequence of the wild-type strand (line 2), aligned with corresponding heterozygous peaks on the top chromatogram. C, Chromatogram from sequencing of reverse strand in the affected member of family G (top) and control samples (bottom). A heterozygous 1-bp insertion leads to a frameshift (shaded sequence), as compared to the wild-type sequence.

Figure 3

Comparison of noggin sequences among wild-type human noggin (line 1), among c.328C→T and c.252-253insC mutations (lines 2 and 3, respectively) that cause stapes ankylosis with broad thumbs and toes and hyperopia, and among previously reported mutations that cause SYM1 (c.386T→A [line 4]) and SYNS1 (c.58delC [line 5]). Shading indicates novel amino acids caused by frameshift mutations. Asterisks (*) indicate stop codons. Bullets (•) indicate conserved cysteine residues.